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Shortages of life-saving drugs are a regulatory and industry concern. Proper process development may help to ensure drug supply.
Editor's Note: An abbreviated version of this article was published in Pharmaceutical Technology Europe's January 2019 print issue.
Drug shortages are one of the most talked about topics in bio/pharma in recent years. External factors such as natural disasters and regulatory pressures, over which pharmaceutical companies might have little control, can contribute to drug shortages. Internal factors, such as failure in process controls, can and should be addressed by the pharmaceutical industry. Robust process development can help ensure that life-saving medicines reach patients.
Chris Moreton of FinnBrit Consulting and Susan J. Schniepp, executive vice-president of Post-Approval Pharma and Distinguished Fellow at Regulatory Compliance Associates, discuss how poor process design can affect the supply chain and the pitfalls some pharma companies fall into.
PharmTech: What are some common pitfalls pharmaceutical manufacturers face when developing manufacturing processes for the manufacture of small- or large-molecule drugs?
Schniepp (Regulatory Compliance Associates): I think one of the major pitfalls that affects the development of a robust manufacturing process is consideration regarding the equipment used, not only in the development of the process, but also in the transfer of the process to various manufacturing sites. I think this pitfall applies to both large- and small-molecule development. The new products are developed with consideration to the use of modern equipment. When these products get transferred from the development arena to the manufacturing arena, the equipment might not be comparable. The manufacturing facility may have older versions of the necessary equipment for producing the product, which could result in problems during transfer of the process. In some cases, the older equipment may require more human interaction, which could compromise the ability to meet the operating requirements specified in the original process. This would prompt changes to the original process that might significantly impact the efficiency of the manufacturing process and create deviations that need to be investigated to assure the product is safe to be released. Some process changes could also result in regulatory changes requiring prior approval before they can be implemented.
Moreton (FinnBrit Consulting): I cannot comment on big pharma, but for small pharma/start-ups working with small molecules, common pitfalls include insufficient understanding of the limitations of the API, excipients, and processing. The questions that should be asked for any pharmaceutical formulation and process development project are:
PharmTech: How can poor process development affect the supply chain?
Moreton (FinnBrit Consulting): Poor process development will most likely lead to stoppages, failed batches, and possibly reduced shelf-life. If the drug product cannot be made on a routine basis, there will likely be supply chain interruptions and patients will suffer. This can apply to both clinical supply and commercial manufacture.
Schniepp (Regulatory Compliance Associates): Poor processes generate deviations, which need to be investigated before product can be released. The more deviations there are associated with the product, the more chance the supply chain will be interrupted. If the original deviations are not investigated thoroughly, [there is the] chance that repeat deviations will occur. The more deviations associated with the process indicates deficiencies in the process. Until these deficiencies are successfully resolved, there is a good chance that the supply chain will be disrupted.
PharmTech: How can poor process development affect a company’s bottom line?
Schniepp (Regulatory Compliance Associates): Poor process development leads to inefficiencies in manufacturing. These inefficiencies lead to delays in product release as well as product rejection. Unless the inefficiencies are effectively resolved and remediated, the company will continue to experience delays in product release and lost revenue from product rejection.
Moreton (FinnBrit Consulting): Problems with supply of the drug product, for whatever reason, will mean that patients may to transferred to alternative products, possibly permanently. This will result in lost sales and thus lost revenue.
During clinical trials, interruptions to the supply of an investigational drug can compromise study results, cause delays in completion of clinical trials, and possibly delay the filing of the marketing application, and thus loss of future revenue.
PharmTech: How often should process development be reassessed? How often does a process change within the lifecycle of a drug product?
Schniepp (Regulatory Compliance Associates): There really is no hard and fast rule to how often process development information should be reassessed. Process deviations, manufacturing equipment changes and investigation results can prompt process changes. The process development information should be used to assure these changes are acceptable to make and do not compromise the quality of the product. Process development information should not stand alone but should be used to support the continuous manufacturing of the product over the product lifecycle.
Moreton (FinnBrit Consulting): Typically, for small-molecule drugs, manufacturing processes for APIs may change, usually to improve yields or reduce the use of toxic solvents, etc. However, this is not so common because the impact on the final drug product performance must be assessed before the change can be implemented.
In my experience, it is very unusual to make changes to a drug product manufacturing process. If they are made, the SUPAC guidance documents (Scale-Up and Post-Approval Changes) would apply in the United States (1–3). Similar criteria would be applied in the European Union.
Looking forward, as quality by design becomes more prevalent, with the move to continuous verification, and with the current emphasis on quality metrics, more reasons for change may be identified as there will be increased scrutiny of data.
PharmTech: Are there new trends in process development? Are companies moving to continuous manufacturing?
Moreton (FinnBrit Consulting): For small-molecule drugs, there is interest in continuous processing. However, it will not be for every product. Smaller-volume products will continue to be batch processed because of the changeover times. It can take up to a week to clean everything associated with a continuous processing line and be ready to run the next product. Thus, continuous processing is really better suited to larger volume products.
Schniepp (Regulatory Compliance Associates): I think the application of quality risk management as part of development activities is one of the major trends for process development. While the concept is not new, it is being applied more routinely in the process development phase to establish appropriate specifications, identify critical process parameters, and establish manufacturing controls. Using information from pharmaceutical development studies potentially helps identify control variations that may arise during processing.
1. FDA, Guidance for Industry: Immediate Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (FDA, November 1995).
2. FDA, Guidance for Industry: SUPAC-MR: Modified Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation (FDA, September 1997).
3. FDA, Guidance for Industry: Nonsterile Semisolid Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation (FDA, May 1977).
Pharmaceutical Technology Europe
Volume 31, No. 1
When referring to this article, please cite it as S. Haigney, "Proper Process Development and Drug Shortages," Pharmaceutical Technology Europe 31 (1) 2019.