Quality by Design (QbD) is a means of developing more robust formulations that will benefit the patient because the quality risks are minimized. Quality Risk Management complements QbD and helps to identify risks and weaknesses associated with systems, development projects and products.
What do we mean by risk? Risk is a very broad concept. The Merriam-Webster dictionary [1] defines risk as:
“… exposure to possible loss or injury …”
In pharmaceutical circles we have the ICH Q9 [2] document, Quality Risk Management, which defines risk as:
“The combination of the probability of occurrence of harm and the severity of that harm.”
In the context of excipients, what do we actually mean by risk and harm? As with all pharmaceutical operations and materials, ultimately we mean risk to the patient: risk of overdosing, suboptimal dosing, harm due to contamination or adulteration, etc. This is the trust the pharmaceutical industry has with the patient, that the pharmaceutical products we manufacture will do a lot of good (cure a disease, improve the quality of life, help in a diagnosis, etc.), and very little harm; the least harm possible. I have stated it in this way because all drugs and drug products have associated risks, e.g. side-effects. To paraphrase Lord Scowen, a former chair of the UK’s Committee on Safety of Medicines, “Show me a drug without side-effects, and I will show you a useless drug!” Lord Scowen was, in effect, restating Paracelsus who, over 400 years ago, noted that everything is harmful; it is only the dose that determines whether it is safe or not. Or put another way, the difference between a drug and a poison is the dose, and how it is administered. Botulinum toxin is one of the most toxic natural materials known, yet it is used at a very low dose, probably on a daily basis, in cosmetic surgery.
The risk that we refer to in Q9 is the risk that we inadvertently cause harm to the patient because the materials and/or processes that are used to manufacture the patient’s medicine are not adequate for the purpose. In the case of excipients, there are risks from contamination, adulteration and inadequate performance. The key issues are how we reduce those risks to acceptable levels (risk mitigation strategies), and what constitutes reasonable precautions to take to reduce the risks below an acceptable upper limit. The FDA has categorized pharmaceutical products (formulations) into two groups; those that present increased risks because of their route of administration or have a potential to do harm through failure, and those that do not present increased risks from the FDA’s perspective. (However, they do still have associated risks.) According to the FDA’s current thinking there are three groups of products associated with increased risk:
• Parenteral products, ocular products, and products intended for application to open wounds. These products must be sterile and injections must be endotoxin-free. Parenteral injections and products for application to open wounds or compromised skin can by-pass the patient’s natural defense mechanisms, i.e. the skin and gastrointestinal tract.
• Dry powder inhalation systems. These products can fail in use and not deliver the correct dose of drug to the patient leading to an increased incidence and severity of asthma attacks.
• Modified release products, both prolonged release products (also termed controlled or extended release products) where failure can lead to dose dumping and potential overdose, and products targeted for release beyond the stomach where failure will lead to premature release and may result in loss of the active drug, or increased side-effects.
In some instances, the critical issues are process-related, e.g. for parenteral injections. However, in others the properties of the materials used to manufacture the product, the API and excipients, will be critical for the proper functioning of the drug product once it is administered to the patient.
It is not just these categories that are associated with risk; they are associated with increased risk. All types of pharmaceutical product are associated with risk, including immediate release products. The digoxin bioavailability issues in the early 1970s [3] should serve to remind us of the potential to cause harm if we do not adequately assess what we are doing. In the early 70s we did not have the understanding we have today, and the change (increase) in bioavailability caused by changes to the manufacturing process was completely unexpected.
We have also known for some time that excipients obtained from different suppliers are not always truly equivalent. There is a least one literature report concerning the inequivalence of a gelmatrix modified release excipient [4] as was already mentioned in a previous column [5]. There are other reports showing that there can be differences between supplies of very common excipient grades obtained from reputable suppliers [6] leading to changed product performance in some way.
The risks to the patient from the inequivalence of individual excipients have been recognized for some years. What we have not done, perhaps, is looked at the wider implications, and realized that there are potential risks associated with all excipients, and all formulations. For every formulation there will be some excipients that will have a greater potential to cause failure of the formulation in some way, and thus increase the risk to the patient. (In this context, performance may be during manufacture of the drug product, during stability, or after administration to the patient. Changes in any of these may affect the patient’s therapy.)
So how can we reduce the risks associated with excipients? From the author’s perspective, the answer is straightforward, although not necessarily what senior management wants to hear. There is really no substitute for knowing your materials (both API and excipients), and knowing the processes used to manufacture the product. Knowing our excipients, means both technically and logistically; not only how they are manufactured and how they are used, but also how they get from the site of manufacture to the site of use. However, there are a couple of further pieces to the puzzle; we also have to understand how the excipients and processing interact, and what can go wrong and why.
If we now focus on excipients; what are the risks that might impact the patient in some way, and how might we mitigate (reduce) those risks to acceptable levels? Please note we can neither eliminate risk completely, nor can we necessarily mitigate all risks to the same extent, and ICH Q9 implicitly recognizes this in the sections Risk acceptance and Risk control. However, we should try to reduce all risks, especially those that are assessed as being unacceptably high.
The risks related to excipients can include, among others:
• Risk of dispensing and using the wrong excipient
• Risk of dispensing and using the wrong grade of an excipient
• Risk that a particular lot of excipient is outside an unrecognized part of the Design Space (e.g. an interaction that occurs within a particular range of an excipient specification that was not included in the Design of Experiments)
• Risk of obtaining and using an adulterated excipient
The first two items on the above list really come down to the user’s internal quality management system. The latter two items require a lot more effort on the part of the excipient user.
It is up to the excipient user (pharmaceutical product manufacturing site/product license holder) to assess and reduce the overall risk to an acceptable level. The overall risk is the sum of the individual risks, and the individual risks according to ICH Q9 (as stated above) are a combination of the likelihood and severity. ICH Q9 also recognizes that detectability may be a factor in the estimation of a particular risk.
The first part of any approach to risk reduction or mitigation is to assess the potential risks inherent in a particular product (risk assessment), and this must obviously include an assessment of the risks linked to the excipients. This is where ‘know your excipients’ really becomes important, because the more we know and understand about the excipients we use, the better we will be able to assess the potential risks. To emphasize what has been stated above, the knowledge and understanding of our excipients must include both the technical issues and the logistical issues; the logistical issues may also include how the excipient starting material is obtained by the excipient manufacturer.
ICH Q9 emphasizes that risk assessment and mitigation is usually undertaken by multi-disciplinary teams and the document gives examples of the types of people that would make up such teams including [1]:
“… e.g. quality unit, business development, engineering, regulatory affairs, production operations, sales and marketing, legal, statistics and clinical.”
When it comes to excipients, the ‘experts from the appropriate areas’ should also include formulation design and development, and purchasing. Without representatives from these two particular areas, the technical and logistical understanding of excipients will probably be incomplete.
There is a second advantage in having a representative from purchasing as it emphasizes to purchasing the importance of maintaining sources of excipients. Perhaps not in major companies, and perhaps not in all smaller companies, but some purchasing agents do not always understand that there can be disadvantages to lower priced sources of excipients. The switch to an alternate source of a common excipient can cost more in production problems than is saved in the direct cost savings from the purchase of the cheaper source of excipient. However, the purchasing agent’s bonus will be tied to their performance in meeting their targets as a purchasing agent, not in helping the production department meet its targets.
The major problem with excipients is that we do not know enough about them, hence the exhortation above to ‘know your excipients’. Our understanding of the excipients we use is not as good as it should be. We frequently do not know why an excipient performs as it does, and we often do not know enough about excipient composition [7]. On top of this many excipients can be used in more than one type of pharmaceutical formulation, e.g. oral immediate release tablets vs. oral immediate release hard capsules vs. oral suspensions. It seems reasonable to suggest that the critical quality attributes necessary for proper functional performance might be different when the excipient is used in such different applications.So how can we undertake a proper risk assessment and implement appropriate risk mitigation strategies for materials that we do not properly understand? We have to start with the formulation (application), and look at what is likely to be important in that particular context. For example, there is no point in worrying about the compaction profile of an excipient if we are undertaking a risk assessment for a dry powder encapsulation formulation. However, bulk and tapped density and the wetting characteristics probably will be important for dry powder encapsulation (and also for tablet compaction and performance).
Once we know the application we can begin to assemble the necessary information, and to prepare e.g. an Ishikawa diagram (also known as a Fishbone diagram or Cause and Effect diagram) to visualize the process, the inputs and areas of potential risk.
Risk assessments may be carried out at any stage during the product lifecycle. It is a good idea to begin the formal quality risk assessments at the start of a development project, and to continue to update the assessment as the project progresses. Even before we have started our laboratory experiments we can make some very preliminary assessments. For example, for an immediate release solid oral dosage form, we know that there are potential risks for product failure with the use of magnesium stearate as a lubricant. If we are looking to develop a modified release product, we know from the SUPAC Modified Release Guidance that we will need to look especially carefully at the release controlling excipients. (We also need to look at the non-release controlling excipients, and we should not forget this.) This kind of assessment will help us with the initial stages of our development work in a QbD world.
Part of the information necessary for the final pre-launch quality risk assessment is the information obtained through our design of experiments as we move up through the various stages of scale up until we have defined our Design Space that is acceptable to the regulatory authorities.
We have focused on the technical aspects of risks associated with excipients. In recent years it is the non-technical issues associated with excipients (and APIs) that sadly have captured the headlines; glycerin and propylene glycol adulterated with diethylene glycol, heparin adulterated with over-sulfated chondroitin sulfate, and pet food and milk adulterated with melamine. When we look at these incidents there are some common issues (besides greed); inadequate specifications and test methods, lack of specific id test (and often the assay as well), inadequate monitoring of supply chains, etc.
The manufacture and supply of pharmaceutical excipients is a global business, and many excipients are sourced overseas. Raw materials (starting materials) for excipients may be sourced under very primitive conditions. They may be harvested from the land or the sea or may be dug from the ground. When assessing the risks associated with excipients, the excipient raw material supply chain may need to be part of the equation. On-site audits (including third party audits) of the manufacturing site, and the immediate supplier if a distributor is involved, are of paramount importance (80-page questionnaires are no substitute). The use of pedigree documents showing the chain of custody and transportation of materials is another means by which we can assess if there is a risk for adulteration, etc.
However, we must never forget that if we want to reduce the risks from adulteration for our excipients then we need to be vigilant, not just for what has gone before, but also for what may be ahead. No one method will absolutely prevent adulteration, we need to invoke multiple measures and make it less attractive to those committing such frauds. It is not the absolute cost which drives such fraud, but the difference (premium) between industrial and pharmaceutical grades of a material, or the cost benefit obtained by being able to dilute e.g. milk by 50% and still maintain the assay (and price) due to the addition of melamine.
We have not really discussed the question of what constitutes reasonable precautions to take to reduce the risks below an acceptable upper limit. In part, there will be an economic component. The ICH Q9 document2 acknowledges this:
“The amount of effort used for risk control should be proportional to the significance of the risk.”
There is also an ethical component. To paraphrase what was stated above, the patient trusts the pharmaceutical industry to provide robust reliable products that do the maximum amount of good for the minimum amount of harm. If anyone thinks that risk mitigation is too expensive, try having a product that does cause harm to patients. The key is to assess the severity of the risk and to decide what is acceptable in both the short and long term. The image of the pharmaceutical industry has suffered in recent years, mainly because companies have been perceived as having put profit before patient safety. That perception will not be altered if companies continue to be seen to place the emphasis on profits rather than mitigating the risk to the patient.
Quality risk assessment, when used properly, can be a very useful tool in maintaining the quality of pharmaceutical products. Excipients are part of the equation, and the more we know about the technical issues and logistics of our excipients, the better for the patient, the pharmaceutical manufacturer and the excipient manufacturer.
I hope this column has been a useful contribution on ICH Q9 and excipients. The next column will look at Excipient Specifications in the context of QbD.
References
1. The Merriam-Webster Dictionary, Pocket Books, New York, NY, 1974.
2. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline: Quality Risk Management, Q9, Step 4 document dated 09 November 2005.
3. Shaw TRD, The digoxin affair, Postgrad Med J, (1974) 50, (February) 98-102.
4. Shah AC, Britten NJ, Olanoff LS and Baldamenti JN. Gel-matrix systems exhibiting bimodal controlled release for oral drug delivery. J. Controlled Release (1989) 9, 169-175.
5. Moreton RC. Functionality and Performance of Excipients in Quality-by-Design world. Part V: Changes in the Sourcing and Supply of Pharmaceutical Excipients, Am Pharm Rev (2009) 12 (September/October) 12-17.
6. Wambolt E, McKnight C, Turkoglu M and Sakr A. Comparison of Two Microcrystalline Cellulose brands for the Direct Compression of Hydrochlorothiazide Tablets, Pharm. Ind., (1993) 55, 1046-1051.
7. Moreton RC. Functionality and Performance of Excipients in Quality-by-Design world. Part VI: Excpient Composition, Am Pharm Rev (2009) 12 (November/December) 48-51.
Dr. Moreton has over thirty years’ experience in the pharmaceutical industry. He has worked as a formulation scientist developing a variety of different dosage forms, and has experience in the design, development, scale-up, technical transfer and validation of drug products and associated analytical methods, both during clinical development and eventual transfer into commercial manufacture, and working with licensing partners and contractors. He has also worked in QA/QC, Regulatory Affairs and Technical Support in excipients and drug delivery. He is a past Chair of the AAPS Excipients Focus Group, and of IPEC-Americas. He is a member of the International Steering Committee of the Handbook of Pharmaceutical Excipients, and of the USP Expert Committee—Excipient Monograph Content 2. He has authored and co-authored scientific papers and book chapters, and lectured extensively in the areas of excipients, drug delivery and formulation at universities, training courses and symposia in the U.S. and Europe.