Patients, healthcare providers, manufacturers and regulators have an intrinsic expectation for effective and safe injectable drug products. This expectation requires injectable pharmaceuticals to be produced to standards of quality, purity and sterility that is uncompromising. Yet compliance with rigid guidelines is a challenge that continues to elude some manufacturing facilities worldwide. Interpretation of the guidelines for ensuring integrity of injectable drug products can be a daunting challenge for the uninitiated, leading to questioning of the means applied to achieve the standards. Are the quality standards for injectable medicines just too high?

Global Challenges, Patient-level Impact 
Globally, drug shortages are being faced by patients and clinicians, partly due to inconsistent product release and recall decisions related to substandard medicines. The manufacture of sterile injectable drug products suitable for human use is a complex process to ensure compliance with the regulatory expectations conceived to protect patients. Injectable product manufacturers must ensure the necessary quality parameters described within the pharmacopeial standards are met for patient safety.

Substandard injectable products can arise through inadequate production processes including unintentional use of inferior or incorrect APIs or excipients; manufacturing processes that cause contamination or do not adequately ensure sterility; and inadequate packaging design or quality. Ineffective quality-control measures, either on the part of the manufacturer or the client sponsor could allow such defects to remain undetected.

Recent years have seen a number of sites being found not to meet regulators expectations for sterile production leading to lost licenses, operating under restricted manufacturing orders or even being closed. There is much discussion in the industry about these high profile inspection failures at sterile production sites with public awareness and sensitivity heightened by the incredibly sad loss of life when things go horribly wrong, which they have done in recent years. Many injectable drugs are used to treat patients who may already be immune compromised or with complex medical history meaning in particular the sterility assurance of such products is critical.

Supply Chain Integrity
Product integrity must be ensured throughout the supply chain with full traceability of materials going into manufacture of medicinal products. Regulators in the EU and U.S. require that marketing authorization holders (MAHs) for medicinal products ensure that appropriate GMP and GDP is applied to the manufacture and distribution of excipients.

An international GMP and GDP Certification Scheme for Pharma Excipients EXCiPACT launched in U.S. as a voluntary international certification scheme designed and developed to assure cGMP and cGDP standards are being used in the manufacture and supply of pharmaceutical excipients.

In the EU, March 2015 saw a new version of Eudralex Volume 4, Annex 15 published which will come into effect on October 1, 2015. The guidelines include the formalized risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use, which mandates assessment of all excipients for authorized medicinal products for human use by March 21, 2016.

Guidelines on principles of Good Distribution Practice of active substances for medicinal products have also been published and come into operation on September 21, 2015.

Ensuring traceability of materials going into manufacture of medicinal products is becoming easier and regulatory guidance more clearly defined.

The regulatory guidelines for the manufacture of sterile drug products aseptically also includes expectations for process qualification to demonstrate aseptic assurance by media simulation, rigorous environmental controls and area monitoring, air handling systems set-up and maintenance, and equipment validation to name just a few of the key equipment, facilities and utilities compliance requirements. A sterile CMO’s facilities must exhibit compliant quality management systems in routine operation, which fundamentally comes from facility design influenced by sound experience of aseptic manufacturing and operation of multi product sites. More recently, CMO’s have been touting about the assistance they have received from regulators in facility designs, expansion and future proofing. This engagement of regulators and industry will over time raise compliance to the standards and reduce the grey areas for interpretation.

Client Conflict
For a CMO (contract manufacturing organization), the responsibility for compliance with regulatory guidelines cannot be underestimated. This is the foundation of their business after all. Drug developers and companies seeking to bring new treatments to market often work with limited budgets and aggressive timelines with product availability and pricing fundamental to their business viability. The cost of quality compliance is high and it’s not just about a transactional purchase of a product, since its certificate of conformance is essentially what is being purchased from a CMO.

To remain in business, any business, a company must meet the requirements of the customer and meet their expectations in terms of product or service performance, cost and quality.

An interesting paradigm exists when conflicting expectations arise between a CMO and its client who questions the necessity to undertake certain activities such as raw materials testing, security tags on shipments, analytical method validation, temperature monitoring during storage and shipment. Activities within the quality control framework for assessment product compliance to agreed specifications for certification and release for human use.

Shades of Grey
Control and monitoring of GMP standards by national drug regulatory agencies in the U.S. and UK are well defined and upheld by the law. In ensuring acceptable quality at the drug manufacture and quality control levels the pick and choose approach to applying the guidelines is not an option however there are many grey areas where interpretation is necessary.
Navigation of these grey areas or interpretation of the guidelines specifically in the manufacturing process and assurance is the value an experienced yet pragmatic CMO can bring to its clients and patients. Some key points and advice on grey areas:

• Why do you need to test the Identity of incoming raw materials when the supplier provides a certificate of analysis? Asking this question reveals a misunderstanding of the purpose of the ID test at receipt. The ID test is required to give   1) assurance that what the supplier has certified and believes they have dispatched is actually what is received and 2) ensure that the material supplied to manufacture as available for use is correct. The most common recorded issue is one of mis-labelling of product by the supplier or during quarantine at site, both resulting in potential use of the wrong material in manufacture. This is why the sample MUST be taken from each container of the received material and this is a clear requirement of GMP.
• We have an analytical method we used in house for pre-clinical work, can we use this for QC release testing? Maybe but unlikely. Testing used for release must be performed using a fully validated method (unlikely for to have been done to the correct ICH standard for pre-clinical). Also it must be performed at an MHRA approved laboratory (if based in the UK), which is named on the releasing license. So, if the method has been fully validated, the client has an MHRA approved laboratory (or equivalent) and we place a variation to include them on our license then yes. In reality it is more efficient to arrange a method transfer and subsequent validation at one of our named CROs.
• Endotoxin and sterility testing was validated on our other similar product, do we really need to validate it again on this product? Yes. The regulations on this are quite clear for sterility. Any change of formulation or presentation e.g. fill volume, or change in testing laboratory requires revalidation. The regulations for endotoxin testing are not so explicit but the regulatory expectation is that the same rules apply.
• Our API manufacturer doesn’t use security tags on shipments so why do you need them?  This is a much debated issue. The GMP regulations state that the receiving company is responsible for checking to ensure no ‘evidence of tampering or contamination’. There is no regulatory stipulation for numbered security tags but this is the best way to ensure compliance with this regulation. In reality, if this is proving prohibitive, then scaled down controls e.g. oversigned security tape, photographs at dispatch etc., can be agreed with the client.

The key thing to take away from all of this is work in collaboration with your CMO using their expertise, engage with the regulatory authorities if required and take no chances.

The issue of low-quality medicines arising through poor manufacturing processes and poor regulatory oversight should be tackled with high-level government commitment to supporting national drug regulatory agencies and their consultation with manufacturers on application of the standards designed to assure patient safety.

So, are the quality standards for injectable medicines just too high? No, they have been developed and evolved to address and mitigate risk in production processes and supply chain integrity. Those outsourcing the manufacture of injectable products must have trust in their CMO to interpret, adopt and rigorously apply quality standards fit for the highest risk medicinal products and patients. There is simply no place for taking chances and cutting corners in the world of sterile manufacturing. 

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Founder and chief executive officer of Symbiosis, Colin MacKay manages all aspects of the company’s day-to-day operations and drives strategic development. With over two decades of experience in the life science industry working for small and large organizations at an international level, Colin has spent most of his career helping clients overcome drug development challenges within the sterile manufacture of pharmaceuticals.