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The author of this article has observed while conducting ISO audits that pharmaceutical industries have already begun to implement GDP, based on The Central Drugs Standard Control Organisation (CDSCO) draft guidance document on GDP for pharmaceutical products. An overview of this draft guidance document has been exemplarily given in the Pharmabiz dated April 13, 2024.
In February 2020, the author had an opportunity to conduct training on GDP for a major distributor of pharmaceutical products in Colombo, Sri Lanka. The training was based on the guideline for GDP released by the National Medicine Regulatory Authority (NMRA), Sri Lanka in August 2019. The NMRA guideline defines GDP as "the measures that need to be considered in the storage, transportation, and distribution of any registered product and its related materials such that the nature and quality intended is preserved when it reaches the consumer". CDSCO states in the GDP draft document that “to maintain the original quality of pharmaceutical products, every party involved in the distribution chain has to comply with the applicable requirement. Each activity in the distribution of pharmaceutical products shall be carried out according to the principles of GDP as applicable.” The author has observed that pharma companies that follow Good Manufacturing Practice (GMP) have an excellent Quality Management System (QMS) for raw materials, process, and finished products. Some pharma companies also have procedures for selecting transport companies for transporting the finished product. However, most of these pharma companies do not have concrete procedures to ensure that the quality of the drugs does not deteriorate during transport.
CDSCO declared over 5 per cent of drug samples tested in November 2023 and February 2024 were spurious. A document of WHO published in 2017 on the Member State Mechanism on substandard/spurious/falsely-labeled/falsified/counterfeit (SSFFC) medical products has outlined a plan for preventing, detecting, and responding to actions, activities, and behaviours that result in SSFFC medical products. Now, the terminology, substandard/spurious/falsely-labeled/falsified/counterfeit medical products is replaced with ‘substandard and falsified’ medical products. This means a falsely labeled medical product is considered a falsified’ medical product. The substandard and falsified medicinal products entering global supply chains have become a serious threat to human life today. The current trend of e-commerce further aggravated the problem. Through e-commerce medicines can be bought easily, often from unauthorized sources. Unknowingly buying counterfeit drugs via e-commerce is common even in developed countries like the US. For example, in 2019, a Maryland woman received a counterfeit supplement from Amazon.com. The actual seller was a third-party site. Amazon realized later that the drug sold to her was counterfeit, and refunded the amount. Till then she had been consuming the supplements daily. The Wall Street Journal investigation team discovered in 2019 that many medicinal products displayed on Amazon's website were counterfeit or falsified. The US FDA issued a warning letter to Amazon.com, Inc. in 2022. In the letter, the US FDA stated that it has purchased mole and skin tag remover products on Amazon.com. The products were not evaluated by the US FDA for safety, efficacy, or quality, nor did they have US FDA approval. The US FDA clearly mentioned in the letter that it is Amazon's responsibility to ensure that all requirements of Federal Law, including US FDA regulations, are met. In India, e-pharmacies of medicines are on the rise. It has been reported that in medicine consumers the preference for e-pharmacy rose from 23% in 2013 to around 59% in 2018. To ensure quality medicines are sold on this e-commerce platform CDSCO has enforced several regulations.
Fake or substandard antimalarial medicines kill as many as 267,000 sub-Saharan Africans every year. Nearly 170,000 sub-Saharan African children die every year from unauthorized antibiotics used to treat severe pneumonia. Traffickers, smugglers, and manufacturers are responsible for these tragic incidents.
WHO defines GDP as ‘that part of quality assurance that ensures that the quality of a pharmaceutical product is maintained by means of adequate control of the numerous activities which occur during the distribution process, as well as providing a tool to secure the distribution system from falsified, unapproved, illegally imported, stolen, substandard, adulterated and/or misbranded pharmaceutical products. The routes through which counterfeit drugs enter the supply chain are many. For example, the ingredients used in the drug are not from certified sources, drugs may travel through several trading companies (the companies do not ascertain quality before they reach final destinations), corrupt players in the supply chain (they are involved in contaminating, substituting or mislabeling products in the supply chain), false paperwork (ingredient/drug manufacturers pose successfully as legitimate pharmaceutical companies with the help of false paperwork), fictitious companies (the counterfeiters disguise their activities, eg., establishing fictitious businesses and front companies), border controls are not effective (controls focus on the movement of people and products over the borders, but does not stop counterfeit drug), etc.
Manufacturing a drug under GMP does not mean that the drug reaches the patient with the required quality. Several things may go wrong during the transport. The most important thing that can affect the drug during transport is the environmental condition to be maintained in the transport vehicle, particularly temperature and humidity. In 2017, Baxter International was forced to withdraw Intralipid 20% IV fat emulsion as it was exposed to subfreezing temperatures while shipping to a distribution facility. When frozen, the product’s emulsion droplets enlarge, forming aggregates that can obstruct pulmonary circulation, leading to serious health problems and possible death.
The author feels that the pharma companies already established procedures for transporting medicinal products can implement GDP prescribed by CDSCO with less effort. For this the QC’s responsibilities can be expanded with the inclusion of additional responsibilities like checking the containers of incoming medicinal products for damage, ensuring the containers are cleaned before storing, securing materials in a manner in the transport vehicle so that unauthorized access is prevented (also to provide evidence of unauthorized access), ensuring that materials are stored and transported in accordance with procedures in such a way that the identity of the materials is not lost and the material does not contaminate other materials, ensuring that appropriate documentation is available so as to permit traceability throughout the distribution activity, ensuring that adequate precautions have been taken for spillage/breakage/misappropriation/theft, ensuring that temperature and relative humidity conditions are maintained and continuously monitored throughout the transport, establishing procedure for recording, reporting and investigating any damage to containers during transit, ensuring that loading area and vehicle are free from dust, rodents, vermin, birds and other pests, ensuring that measures are taken to prevent unauthorized persons from entering/tampering with vehicles/ equipment, and to prevent theft, and so on.
The US FDA enacted the Drug Supply Chain Security Act (DSCSA) in 2013. Recently the US FDA has published several documents related to DSCSA. One of the documents outlines steps to achieve electronic tracing of products at the package level to identify and trace certain prescribed drugs. DSCSA also directs the US FDA to establish national licensure standards for wholesale distributors and third-party logistic providers. The United States Pharmacopeia has expanded its series of good storage and GDP by including risks and mitigation strategies for the storage and transportation of finished drug products, mean kinetic temperature in the evaluation of temperature excursions during storage and transportation of drug products, monitoring devices-time, temperature, and humidity, temperature mapping for the qualification of storage areas, qualification of shipping systems, transport route profiling qualification, information systems for distribution validation/verification studies. Recently, the US FDA has sent out several warning letters addressing GDP-relevant issues.
Establishing robust procedures for product recall and conducting mock product call exercises are important aspects of GDP. It is expected that every licensed manufacturer, importer, and wholesaler should have a product recall procedure.
If a drug is unable to reach the end user, the patient, with the established therapeutic quality and safety whatever GMP system used to manufacture the drug does not serve the purpose. Adherence to GDP is equally important to adherence to GMP. Similarly, e-pharmacies should make sure that medicines sent to the buyer are from GMP facilities, stored in appropriate environmental conditions by the stockists, and sent to the customer in proper containers/packings. Also, make sure that quality is not affected during the transit.
(Author is Director-Toxicology, PNB Vesper Life Science, Kochi, Kerala-682 011)
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