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Regulatory bodies around the world are now revising legislation, regarding counterfeit medicines, good manufacturing and distribution practices, and risk management.
In considering the pharmaceutical supply chain and management of change, there are two particular areas in the processing cycle that can expose a company's products to risk. The first is at the start of the chain, when there is potential for contamination of raw materials—active or inactive. The second is at the end of the chain, when the finished product, sealed in its final container, is distributed. This article addresses both topics, their overall management, and individual product control strategies that a company might consider.
Counterfeiting medicines presents a relatively safe way of generating money. Criminal organizations, with terrorists high on the list, are constantly seeking new ways to obtain funds. Sadly, the pharmaceutical marketplace has become a setting for them to do so. Active pharmaceutical ingredients (APIs) present an opportunity to infiltrate the system early in the supply chain, generating high income. With a little analytical knowledge and understanding of the types of incoming tests performed on materials at finished dosage form manufacturers, counterfeiters are finding sophisticated ways of introducing their fakes into the genuine supply.
Counterfeit medicines are those that are deliberately contaminated or misbranded and constitute part of a wider group of substandard pharmaceuticals. Substandard products are manufactured beneath minimum recognized standards of quality and thereby pose serious hazards to the end-user. Unlike counterfeits, which are deliberately and fraudulently introduced into the supply chain, substandard medicines are often the outcome of incompetence or negligence. In either case, pharmaceutical companies and regulators alike have an interest in preventing these phenomena.
Recent estimates from the World Health Organization (WHO) place the pharmaceutical counterfeiting trade as high as 10% of overall commerce in medicinal products. The horrendous growth rate of this bogus industry is set to overtake that of genuine pharmaceuticals by 2010. In 2006, WHO set up a global task force known by the acronym IMPACT, which stands for International Medical Products AntiCounterfeiting Taskforce. The taskforce suggested that key areas of activity tied to combatting counterfeiters include legislation, regulations, enforcement, technology, and communication strategies. However, WHO has stated that the primary driver for anticounterfeit measures should be regulatory agencies and enforcement activities. The US Congress has adopted a similar approach, mostly recriminatory, toward the US Food and Drug Administration subsequent to the heparin recall earlier this year. However, regulators and their regulations, while essential in reducing it, will never be able to entirely prevent criminal activity.
The primary intent of good manufacturing practice (GMP) and good distribution practice (GDP) regulations is to provide minimum standards for those manufacturers and distributors interested in setting up effective quality systems and to minimize the likelihood of substandard products caused by negligence or lack of knowledge. Where there is intent to defraud, it is industry that needs to proactively design preventive measures into its supply chain through company policies and procedures and effective training of concerned personnel. The self-interest of genuine pharmaceutical manufacturers to seal off potential penetration points for counterfeit product suggests that the ICH (International Conference on Harmonization) approach, in which legislators and industry representatives work closely to develop guidance, might result in the implementation of rapid and effective measures against those who have the potential to harm industry. Indeed, US regulators have already reached out to industry and set up at least one such task force, resulting in the Sept. 2008 PDA/FDA Supply Chain Conference held in Washington, DC.
It is therefore appropriate that anticounterfeiting measures for the distribution chain be designed into a product as part of a company's control strategy. These measures can include electronic tagging, tamper-evident seals, holograms, and so forth, as a standard for both finished product and active substances as well as industry investment (possibly in conjunction with the electronics and security industries) in development of novel measures.
The 2008 heparin recall resulted from contamination of the raw material with large amounts of chondroitin, which is difficult to detect, especially if a company is performing reduced testing (identity only) on most incoming batches. Whether the contamination was deliberate has not yet been firmly established, although there are indicators that it might have been. FDA has not come out of the episode smelling of roses–owing to a "computer glitch" that they inspected the wrong site. In its defense, FDA claims an unmanageable situation whereby the agency is expected to regulate a supply chain spreading across five continents with resources that barely suffice for the US alone. Where does this leave industry?
Consider the following situation: Your company registered a new finished product in various markets worldwide. The applications are pending. Your purchasing department wants to change the supplier of either an active or key inactive ingredient because it found a new supplier who can give a per kilogram price that is 30% of the current cost. How will you handle the change?
ICH Q10 Pharmaceutical Quality System, finalized in June 2008, states: "The change management system ensures continual improvement is undertaken in a timely and effective manner while providing a high degree of assurance there are no unintended consequences of the change."
In the current commercial environment, companies are constantly looking for ways to cut costs. One of the areas where, at first glance, substantial savings might be made is in sourcing of active and inactive ingredients. Your purchasing department, for example, may find from a quick Internet search that there is no shortage of suppliers, including manufacturers and, of still greater concern, brokers or distributors. The quality department, understanding that cost savings cannot be calculated by a price-per-kilogram comparison, is in a dilemma as to how to manage such a request. The request cannot be ruled out without investigation. A risk assessment might be a useful approach. A better option may be a product control strategy that assesses the hazards associated with changing a manufacturer of a raw material on a product-by-product basis during development, identifies potential points of entry for counterfeits, and aggressively designs controls into the supply chain.
A product control strategy, according to ICH Q10, is defined as:
A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product, materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.
Using the Ishikawa (fishbone) diagram, an initial identification of risk associated with sourcing of raw materials can be constructed. Figure 1 provides one example of a partial assessment. To conduct a complete analysis, a multifunctional team should be established, preferably including persons from the development, production, quality assurance/quality control, laboratory, and purchasing departments. The diagram can then serve as a basis for performing a risk assessment such as the failure mode and effects analysis (FMEA) technique, for each point that was identified or for those points which the team designates as significant concerns. For example, microbial issues might be related to potential uses of an API by the end-user. Therefore, as a purchaser, one of the questions to ask the supplier or manufacturer is whether it has performed a risk assessment for microbial control of its process. ICH Q6: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products provides decision trees for setting microbial specifications, so this could help the API vendor in performing its risk assessment. However, your company may need the vendor to refine the assessment based on your intended use (e.g., their current customers have used the product in solid oral dosage forms but your company plans to use it for parenteral administration; therefore, your microbial requirements will be more stringent).
An initial questionnaire can provide useful insight into the quality system of the vendor and regarding other products manufactured by the vendor at the same site. For example, does the vendor have a risk management policy? Does it produce beta-lactam products, potent hormones, or pesticides? Ask about nonpharmaceutical activity at the same site. What type of quality system does it have in place and who releases batches? The initial decision to continue to investigate or reject the supplier out of hand should be based on the outcome of this initial risk assessment.
After the risk assessment, your company will need to perform an on-site audit which should be planned with precision. Your time on site is going to be limited, so obtaining as much information about the company as possible upfront will be beneficial.
Try to find out whether personnel at your potential supplier understand quality issues. Take a draft agreement with you addressing responsibilities (e.g., notifying you about changes, reprocessed or reworked batches, and major process deviations) that could result in a different impurity profile if not followed. Before approving a new vendor, make sure the new supplier/manufacturer (and you will need full information about both if using a distributor) is a quality partner willing to listen to and accommodate your GMP needs.
Ask the supplier whether it has other manufacturing sites before you leave for your audit. You need to visit any site that is a potential supplier. Do not assume that if one site meets your requirements, the other(s) will be equivalent.
Think about what the change to a new supplier will involve within your company regarding approved and pending applications and how they will be handled. Different markets take different lengths of time to approve variations or amendments to licensing submissions, so a global pharmaceutical company could find itself continuing to purchase material from its previous supplier for three to, in extreme cases, five years. As a result, the compay ends up having to segregate product destined for various countries. Additional stability studies and process validation may be needed as well. These activities will have to be handled as part of the change management plan.
At the other end of the spectrum are distribution issues. GDPs constitute the part of quality assurance that ensures products are consistently stored, transported, and handled under suitable conditions as required by the marketing authorization or product specification. Storage, transportation, and handling are obvious points for entry of counterfeits into a supply chain and therefore require careful control. Although quality systems generally have well developed procedures in place for managing changes to the starting materials supply chain, the distribution chain may be a different story. Granted, in the past few years, distribution agreements have become far more sophisticated and commonly include a quality/technical agreement, but you need to ask yourself whether the resolution is sufficient. With distribution being a global activity in today's market, there are local laws and regulations that need to be addressed that may require relabeling or repackaging and again offer an opportunity for substitution of the real product with a counterfeit. Tamper-evident seals may not be a solution if the patient insert needs to be replaced with one in the local language. A formal risk assessment (e.g., Ishikawa follwed by FMEA), can allow your cross-functional team to assess potential hazards in the distribution chain. A few items to be considered include:
Having completed your analysis, take time to consider the unlikely. For example, after you put procedures in place to control all identified risks and sign a distribution agreement with your chosen contractor, how will your company handle a new distributor trying to grab the business? How much time and effort will your quality department need to invest to place the necessary controls in place with the replacement?
In the case of change management and sourcing of starting materials and contractors for distribution, companies would be well placed to remember one of Deming's 14 principles for quality management:
End lowest tender contract. Cease the practice of awarding business solely on the basis of price tag. Instead require meaningful measures of quality along with price. Reduce the number of suppliers for the same item by eliminating those that do not qualify with statistical and other evidence of quality. The aim is to minimize total cost, not merely initial cost, by minimizing variation. This may be achieved by moving toward a single supplier for any one item, on a long term relationship of loyalty and trust. Purchasing managers have a new job, and must learn it.
In a global environment, the hazards that exist at both ends of the supply chain require drug manufacturers to be cautious with regard to managing change. Unfortunately, drugmakers must also consider potential rogues within the growing counterfeiting industry waiting to make a fast buck. The current business environment obliges quality professionals to be willing to make necessary changes when proved justified. The way to manage these changes effectively is through partnering: first, partnering internally between your quality and purchasing departments; second, partnering externally with new vendors by ensuring they are on the same page with respect to quality systems. If appropriate risk assessments are made and controls are put in place based on the outcome, the changes should move forward smoothly and efficiently to the benefit of all parties.
Karen Ginsbury is president of Pharmaceutical Consulting Israel Ltd., firstname.lastname@example.org.