By Ray Nims
Pharmacodynamics is the study of a specific effect of a drug as related to drug concentration at the putative active-site for that effect. Pharmacodynamics is sometimes used to model quantitatively the effect of a drug over time as drug concentration at the active-site rises and falls. Another type of pharmacodynamic study entails exposing the animal or in vitro system to graded doses of a drug and monitoring the effect associated with each active-site concentration. From the latter type of study, one is able to estimate both potency for the effect (given in terms of the active-site drug concentration at the half-maximal effect for that drug, or EC50) and its efficacy (given in terms of percentage of maximal response compared to other drugs causing the same effect through the same mechanism). In receptor theory, EC50 is considered to reflect the affinity of the drug for a receptor, while efficacy is a measure of the bound drug’s ability to cause the specific response.
The induction of drug-metabolizing enzymes, such as the cytochromes P450, may be considered to represent an effect of a drug or xenobiotic. It is common for investigators to measure such induction at one or a few dose levels and to compare the resulting enzyme induction with that of a prototype inducer. These comparisons are sometimes described in terms of the test xenobiotic causing “strong” (“potent”) or “weak” induction in comparison with the prototype inducer. As already pointed out quite elegantly by D. A. Smith and coworkers (Letter to the Editor: The Time to Move Cytochrome P450 Induction into Mainstream Pharmacology is Long Overdue. Drug Metab. Dispos. 35:697-698, 2007; http://dmd.aspetjournals.org/cgi/content/full/35/4/697), such statements are both misleading and inaccurate. As with any drug effect, enzyme induction must be described in terms of both potency and efficacy. It is possible for an inducer to be very potent but to display little efficacy. In fact, a xenobiotic having high potency and little or no induction efficacy might represent a competitive inhibitor for this effect. In contrast, there may be inducers which are very effective, but not very potent.
It is possible for efficacy and potency for enzyme induction to be estimated on the basis of studies using intact animals, provided that certain assumptions are made (e.g., that total plasma drug concentration is a suitable proxy for drug concentration at the induction active site, which cannot be sampled directly). An example of such a study is that of R.W. Nims and coworkers (Comparative Pharmacodynamics of Hepatic Cytochrome P450 2B Induction by 5,5-Diphenyl- and 5,5-Diethyl-substituted Barbiturates and Hydantoins in the Male F344/NCr Rat. J. Pharmacol. Exp. Therap. 270: 348-355, 1994; http://jpet.aspetjournals.org/cgi/content/abstract/270/1/348). A more straightforward approach is offered through in vitro enzyme induction studies, in which enzyme induction can be related to drug concentration in the culture medium (e.g., Kocarek and coworkers: Differentiated Induction of Cytochrome P450b/e and P450p mRNAs by Dose of Phenobarbital in Primary Cultures of Adult Rat Hepatocytes. Mol. Pharmacol. 38:440-444, 1990; http://molpharm.aspetjournals.org/cgi/content/abstract/38/4/440).
Measurement of the induction of the cytochromes P450 and other drug-metabolizing enzymes following drug treatment in animals and humans is an important aspect of drug characterization. The studies should be performed and reported in a manner consistent with other drug effects, that is, in a manner consistent with the principles of pharmacology.
Friday, November 6, 2009
Thursday, October 29, 2009
Got animal-derived materials? Part 2
By Ray Nims
As part of a formal animal-derived materials program, biopharma companies must assess the viral and TSE risk associated with materials derived from animals or which have been in contact with animal-derived materials at some point. We have addressed the viral risk within a previous blog installment. Now let’s consider the TSE risk.
TSEs (transmissible spongiform encephalopathies) are fatal diseases believed to result from exposure of a few animal species (including various ruminants, cervids, ungulates, cats, minks, and humans) to “infectious” prion proteins. The infectious proteins (PrPSc) are capable of interacting with and altering the normal prion proteins (PrPc) within the brain and spinal cord, changing the normal proteins to the abnormal form. Since humans have contracted prion disease as a result of consuming tissues from cattle with bovine spongiform encephalopathy (mad cow disease), there is concern about the use of bovine materials and materials from other “relevant species” in the manufacture of biopharmaceuticals.
The EMEA has provided a guidance document (EMEA/410/01 Rev. 2 October 2003; http://www.emea.europa.eu/pdfs/human/bwp/TSE%20NFG%20410-rev2.pdf) describing the requirements for the use of animal-derived materials from relevant animal species (cattle, sheep, goats, and other animals which are naturally susceptible to TSEs but not including humans or non-human primates) in the manufacture of medicinal or veterinary products. The guidance applies to active substances, excipients and adjuvants, raw and starting materials and reagents, and materials which come into contact with products or equipment used to make product. The major point of the guidance is that TSE risk can be minimized, but in many cases not entirely eliminated. Where TSE risk cannot be avoided through elimination of animal-derived materials completely, the guidance provides principles for the minimization of TSE risk which include: the use of low-risk (non-relevant) animal species, the geographical sourcing of relevant species from low-risk regions, the use of low-risk tissues, the use of appropriate slaughter techniques to reduce potential for contamination of low-risk tissues with high-risk tissues, the appropriate oversight of manufacture of the animal products through Quality Assurance and self and external auditing and Quality Control testing, and the implementation of process designs to remove or inactivate the abnormal prion proteins.
Biopharma companies using animal-derived materials are instructed to perform risk assessments on those materials, which take into account the factors described above. The risk assessments must be completed as part of a formalized animal-derived materials program, documented procedurally and executed by staff that are experienced and trained to conduct such assessments. EMEA inspectors will expect to see this formal program in place. Risk assessments for individual raw materials may then be rolled up into a risk assessment for the biopharma product. The rolled up risk assessment may also consider manufacturing steps at the biopharma which may remove or inactivate the abnormal prion proteins, though these, if cited, may need to be validated. Finally, it is expected that companies will conduct a benefit/risk evaluation to assure that any benefits realized by the patient taking the product will outweigh and justify the risk associated with the use of materials derived from relevant animal species.
As part of a formal animal-derived materials program, biopharma companies must assess the viral and TSE risk associated with materials derived from animals or which have been in contact with animal-derived materials at some point. We have addressed the viral risk within a previous blog installment. Now let’s consider the TSE risk.
TSEs (transmissible spongiform encephalopathies) are fatal diseases believed to result from exposure of a few animal species (including various ruminants, cervids, ungulates, cats, minks, and humans) to “infectious” prion proteins. The infectious proteins (PrPSc) are capable of interacting with and altering the normal prion proteins (PrPc) within the brain and spinal cord, changing the normal proteins to the abnormal form. Since humans have contracted prion disease as a result of consuming tissues from cattle with bovine spongiform encephalopathy (mad cow disease), there is concern about the use of bovine materials and materials from other “relevant species” in the manufacture of biopharmaceuticals.
The EMEA has provided a guidance document (EMEA/410/01 Rev. 2 October 2003; http://www.emea.europa.eu/pdfs/human/bwp/TSE%20NFG%20410-rev2.pdf) describing the requirements for the use of animal-derived materials from relevant animal species (cattle, sheep, goats, and other animals which are naturally susceptible to TSEs but not including humans or non-human primates) in the manufacture of medicinal or veterinary products. The guidance applies to active substances, excipients and adjuvants, raw and starting materials and reagents, and materials which come into contact with products or equipment used to make product. The major point of the guidance is that TSE risk can be minimized, but in many cases not entirely eliminated. Where TSE risk cannot be avoided through elimination of animal-derived materials completely, the guidance provides principles for the minimization of TSE risk which include: the use of low-risk (non-relevant) animal species, the geographical sourcing of relevant species from low-risk regions, the use of low-risk tissues, the use of appropriate slaughter techniques to reduce potential for contamination of low-risk tissues with high-risk tissues, the appropriate oversight of manufacture of the animal products through Quality Assurance and self and external auditing and Quality Control testing, and the implementation of process designs to remove or inactivate the abnormal prion proteins.
Biopharma companies using animal-derived materials are instructed to perform risk assessments on those materials, which take into account the factors described above. The risk assessments must be completed as part of a formalized animal-derived materials program, documented procedurally and executed by staff that are experienced and trained to conduct such assessments. EMEA inspectors will expect to see this formal program in place. Risk assessments for individual raw materials may then be rolled up into a risk assessment for the biopharma product. The rolled up risk assessment may also consider manufacturing steps at the biopharma which may remove or inactivate the abnormal prion proteins, though these, if cited, may need to be validated. Finally, it is expected that companies will conduct a benefit/risk evaluation to assure that any benefits realized by the patient taking the product will outweigh and justify the risk associated with the use of materials derived from relevant animal species.
Friday, October 23, 2009
Got Animal Derived Materials?
By Ray Nims
Most biopharma manufacturing processes utilize a few raw materials (including cell substrates, excipients, materials which come into contact with the product, etc.) derived from animals or which have been in contact with animal-derived materials at some point. As part of a formal animal-derived materials program, the biopharma must assess the viral and TSE risk associated with such materials. Let’s consider the viral risk first. From a viral safety standpoint, it is important for each biopharma to consider such ingredients and to be aware of the inherent risk of transmitting virus into the product via the materials. Why? As Genzyme discovered in the spring of 2009 (http://www.genzyme.com/corp/media/GENZ%20PR-061609.asp), viruses can infect the upstream manufacturing processes with results devastating to both the biopharma and to the patients its products are intended to treat. Viral risk mitigation, and regulatory guidance (e.g., EP Chapter 5.1.7: Viral Safety), require that viral risk assessments be performed for animal-derived materials used to manufacture biologics. In this context, raw materials include also excipients, growth media, column packing resins, and cell substrates.
For each product, manufacturers should list the animal-derived materials utilized, and should perform a viral risk assessment for those materials. This assessment considers the animal species and tissue, the processes used to manufacture the raw material, the quality control testing performed on the raw material, and in some cases, the manufacturing process in which the raw material is to be used at the biopharma. Inspectors from the EMEA will not only expect the risk assessments to have been performed and documented, but will expect that the assessment process be formalized into a business practice or standard operating procedure. The staff performing the assessments should be qualified for this task and the assessment team should include staff knowledgeable in virology, viral inactivation and removal, and the manufacturing and purification processes employed for the specific product at the biopharma.
Viral risk assessments completed for individual raw materials may eventually be rolled up into a viral safety assessment for the product per EP Chapter 5.1.7. This product evaluation will also consider other factors, such as the patient profile and route of administration, the cell substrate, the types and pathogenicities of viral contaminants found in the cell substrate and the manufacturing process, the amount of bulk material required for a human dose, and the viral inactivation and removal capabilities of the manufacturing downstream processes.
Most biopharma manufacturing processes utilize a few raw materials (including cell substrates, excipients, materials which come into contact with the product, etc.) derived from animals or which have been in contact with animal-derived materials at some point. As part of a formal animal-derived materials program, the biopharma must assess the viral and TSE risk associated with such materials. Let’s consider the viral risk first. From a viral safety standpoint, it is important for each biopharma to consider such ingredients and to be aware of the inherent risk of transmitting virus into the product via the materials. Why? As Genzyme discovered in the spring of 2009 (http://www.genzyme.com/corp/media/GENZ%20PR-061609.asp), viruses can infect the upstream manufacturing processes with results devastating to both the biopharma and to the patients its products are intended to treat. Viral risk mitigation, and regulatory guidance (e.g., EP Chapter 5.1.7: Viral Safety), require that viral risk assessments be performed for animal-derived materials used to manufacture biologics. In this context, raw materials include also excipients, growth media, column packing resins, and cell substrates.
For each product, manufacturers should list the animal-derived materials utilized, and should perform a viral risk assessment for those materials. This assessment considers the animal species and tissue, the processes used to manufacture the raw material, the quality control testing performed on the raw material, and in some cases, the manufacturing process in which the raw material is to be used at the biopharma. Inspectors from the EMEA will not only expect the risk assessments to have been performed and documented, but will expect that the assessment process be formalized into a business practice or standard operating procedure. The staff performing the assessments should be qualified for this task and the assessment team should include staff knowledgeable in virology, viral inactivation and removal, and the manufacturing and purification processes employed for the specific product at the biopharma.
Viral risk assessments completed for individual raw materials may eventually be rolled up into a viral safety assessment for the product per EP Chapter 5.1.7. This product evaluation will also consider other factors, such as the patient profile and route of administration, the cell substrate, the types and pathogenicities of viral contaminants found in the cell substrate and the manufacturing process, the amount of bulk material required for a human dose, and the viral inactivation and removal capabilities of the manufacturing downstream processes.
Tuesday, October 13, 2009
Outsource it, and fuggedaboutit?
By Ray Nims
Much has been written about the rationales and advantages for outsourcing of manufacturing and/or testing services; about the selection of outsourcing partners; and about the optimization of the pharma/contractor relationship. In any pharma/contractor relationship, there are responsibilities associated with the pharma as well as contractor responsibilities. These include both business as well as compliance responsibilities. The business realities and regulatory expectations associated with the use, by a pharma company, of a contract testing organization must be considered when the decision is made to outsource. A contract testing organization desiring to provide services for a pharmaceutical must be aware of the expectations and responsibilities associated with such a partnership. The optimal and most defensible programs will be those in which the various practices to be described below are formalized within internal Quality Systems, policies, and/or standard operating procedures as well as Quality Agreements.
Responsibilities falling upon the pharmaceutical partner include: 1) the selection of the contract testing lab; 2) commissioning and providing test samples of raw materials and products for method verification (compendial methods) and method qualification (non-compendial methods); 3) instituting of a Quality Agreements, business agreement, and/or confidentiality agreement with the contractor; 4) scheduling and shipping of test samples in accordance with the requirements of the testing lab and the test system; 5) providing in-life guidance and oversight of investigations of unexpected and out of specification results; and 6) ongoing monitoring of the performance of the contract lab and its methods.
Responsibilities primarily falling upon the testing lab include: 1) attaining and maintaining GLP or GMP compliance as appropriate for the intended use of the method; 2) providing assurance that the methods offered will be available to the client over the long term; 3) responsiveness to the sponsoring pharma and adherence to the terms of the Quality and/or business agreements; 4) method validation, verification, and or qualification as appropriate for the intended use of the method; 5) control of reagent, raw material, control, and standard inventory and quality; 6) assuring secure and retrievable data archiving; and 7) retention of staff possessing the appropriate expertise for direction of operators and the methods.
Much has been written about the rationales and advantages for outsourcing of manufacturing and/or testing services; about the selection of outsourcing partners; and about the optimization of the pharma/contractor relationship. In any pharma/contractor relationship, there are responsibilities associated with the pharma as well as contractor responsibilities. These include both business as well as compliance responsibilities. The business realities and regulatory expectations associated with the use, by a pharma company, of a contract testing organization must be considered when the decision is made to outsource. A contract testing organization desiring to provide services for a pharmaceutical must be aware of the expectations and responsibilities associated with such a partnership. The optimal and most defensible programs will be those in which the various practices to be described below are formalized within internal Quality Systems, policies, and/or standard operating procedures as well as Quality Agreements.
Responsibilities falling upon the pharmaceutical partner include: 1) the selection of the contract testing lab; 2) commissioning and providing test samples of raw materials and products for method verification (compendial methods) and method qualification (non-compendial methods); 3) instituting of a Quality Agreements, business agreement, and/or confidentiality agreement with the contractor; 4) scheduling and shipping of test samples in accordance with the requirements of the testing lab and the test system; 5) providing in-life guidance and oversight of investigations of unexpected and out of specification results; and 6) ongoing monitoring of the performance of the contract lab and its methods.
Responsibilities primarily falling upon the testing lab include: 1) attaining and maintaining GLP or GMP compliance as appropriate for the intended use of the method; 2) providing assurance that the methods offered will be available to the client over the long term; 3) responsiveness to the sponsoring pharma and adherence to the terms of the Quality and/or business agreements; 4) method validation, verification, and or qualification as appropriate for the intended use of the method; 5) control of reagent, raw material, control, and standard inventory and quality; 6) assuring secure and retrievable data archiving; and 7) retention of staff possessing the appropriate expertise for direction of operators and the methods.
Tuesday, August 4, 2009
Do You Use Risk Assessments in Auditing?
Audits are a critical component of quality systems, but are they guided by formal assessments of risk to your products? In this world of ICH Q9, can you offer even a semi-quantitative justification for your audit priorities? We have spoken to many people in the industry, and almost all mention a risk assessment being undertaken prior to an audit. But we have not found many people that formalize that risk assessment, or keep it updated from audit to audit. Even fewer communicate their scoring of risk to either their internal clients or the vendor that has been audited.
A new trend in auditing is to use a form of risk assessment both before and after the audit. A popular form is the Failure Modes and Effects Assessment, or FMEA (see, for example, http://www.sre.org/pubs/Mil-Std-1629A.pdf). In a traditional FMEA, risks of failure are identified in a detailed fashion, and scored in three categories related to the failure’s probability, detectability and severity. Scoring is done on a semi-quantitative or relative basis using an arbitrary scale such as 1-10. For an audit, you might use the same categories as they relate to a particular vendor's (or department's) ability to deliver a product or service, failure free. You could organize your FMEA according to the critical quality attributes of the product or service being delivered or according to a list of requirements from a guideline or the CFR's. Your FMEA should receive input from affected departments, and should be used for prioritization of audit items. You should have the FMEA in mind as you conduct your audit, and remember why various items received high prioritization. You may change ratings for probability or detectability based on what you observe. If instead, you confirm your evaluation, you should probe remediations that decrease your firm's primary concern. A remediation that addresses detectability, when the issue was probability, likely won’t mitigate the risk of failure.
When you return from your audit, rescore the FMEA with assessments based on your observations and data that you collected. Make sure that you share your analysis with the stakeholders. And monitor the performance of the vendor until the next audit; the data will help inform your next FMEA.
Do you already use FMEA's in audit preparation and reporting? Let us know your practices.
A new trend in auditing is to use a form of risk assessment both before and after the audit. A popular form is the Failure Modes and Effects Assessment, or FMEA (see, for example, http://www.sre.org/pubs/Mil-Std-1629A.pdf). In a traditional FMEA, risks of failure are identified in a detailed fashion, and scored in three categories related to the failure’s probability, detectability and severity. Scoring is done on a semi-quantitative or relative basis using an arbitrary scale such as 1-10. For an audit, you might use the same categories as they relate to a particular vendor's (or department's) ability to deliver a product or service, failure free. You could organize your FMEA according to the critical quality attributes of the product or service being delivered or according to a list of requirements from a guideline or the CFR's. Your FMEA should receive input from affected departments, and should be used for prioritization of audit items. You should have the FMEA in mind as you conduct your audit, and remember why various items received high prioritization. You may change ratings for probability or detectability based on what you observe. If instead, you confirm your evaluation, you should probe remediations that decrease your firm's primary concern. A remediation that addresses detectability, when the issue was probability, likely won’t mitigate the risk of failure.
When you return from your audit, rescore the FMEA with assessments based on your observations and data that you collected. Make sure that you share your analysis with the stakeholders. And monitor the performance of the vendor until the next audit; the data will help inform your next FMEA.
Do you already use FMEA's in audit preparation and reporting? Let us know your practices.
Tuesday, June 23, 2009
Why is Quality by Design so heavy with statistics?
Why is the literature on Quality by Design so laden with statistics and experimental design space jargon? After all, the definition of the term “design” doesn't seem to include the analysis of messy data leading to rough correlations with results that are valid only over a limited range. So what gives?
The idea behind QbD was to use mathematical, predictive models to predict process outcomes. This concept can be applied directly to simple unit operations, such as drying, distilling, heating and cooling. However, unlike in the petrochemical business, the thermodynamic properties of most active pharmaceutical ingredients are not known and are difficult to measure. The unit operations used to manufacture common biotechnology products, such as cell culture, chromatography and fermentation have been modeled, but the models are very sensitive to unknown or unmeasureable adjustable parameters. The batch nature of these operations also makes their control difficult, as classical control theory relies on the measurement of an output to make an adjustment to an input to correct the output back towards the design specification.
Since there does not appear to be a clear path to using models, an approach has been chosen that emphasizes getting as much phenomenological information from as few experiments as possible. This is the Design of Experiments approach, where input conditions or operating parameters are systematically varied over a range and the process outputs measured, with statistics used to deconvolute the results. The combined ranges tested become the “design space”, and the process performance outputs with the variations closest to the process failure limit become the critical performance parameters. The results are useful, but only within the design space, and only with the certainty that the statistics report. Also, since the results are phenomenological, the effect of scale is often unknown.
The statistical approach is acceptable, and for the immediate future it's probably the best that we can expect. But the focus on this approach seems to drown out the more pressing need for good process models and physical properties data. These are the elements that allowed the petrochemical and commodity chemicals industries to scale up processes with assurance that quality specifications would be met. There are countless models available for bioprocessing's more complicated unit operations, but they have parameters that we don't know and can't calculate from first principles. There is no question that we need to find ways to collect this data, and a commitment to publish or share it. There are also simpler unit operations that we can model, scale up and scale down with complete assurance. These include operations such as mixing and storing solutions, filtration, diafiltration, centrifugation and some reactions. We shouldn't let the more complicated operations that still require statistical DOE approaches prevent us from applying the true principles of QbD to our simpler unit operations.
The idea behind QbD was to use mathematical, predictive models to predict process outcomes. This concept can be applied directly to simple unit operations, such as drying, distilling, heating and cooling. However, unlike in the petrochemical business, the thermodynamic properties of most active pharmaceutical ingredients are not known and are difficult to measure. The unit operations used to manufacture common biotechnology products, such as cell culture, chromatography and fermentation have been modeled, but the models are very sensitive to unknown or unmeasureable adjustable parameters. The batch nature of these operations also makes their control difficult, as classical control theory relies on the measurement of an output to make an adjustment to an input to correct the output back towards the design specification.
Since there does not appear to be a clear path to using models, an approach has been chosen that emphasizes getting as much phenomenological information from as few experiments as possible. This is the Design of Experiments approach, where input conditions or operating parameters are systematically varied over a range and the process outputs measured, with statistics used to deconvolute the results. The combined ranges tested become the “design space”, and the process performance outputs with the variations closest to the process failure limit become the critical performance parameters. The results are useful, but only within the design space, and only with the certainty that the statistics report. Also, since the results are phenomenological, the effect of scale is often unknown.
The statistical approach is acceptable, and for the immediate future it's probably the best that we can expect. But the focus on this approach seems to drown out the more pressing need for good process models and physical properties data. These are the elements that allowed the petrochemical and commodity chemicals industries to scale up processes with assurance that quality specifications would be met. There are countless models available for bioprocessing's more complicated unit operations, but they have parameters that we don't know and can't calculate from first principles. There is no question that we need to find ways to collect this data, and a commitment to publish or share it. There are also simpler unit operations that we can model, scale up and scale down with complete assurance. These include operations such as mixing and storing solutions, filtration, diafiltration, centrifugation and some reactions. We shouldn't let the more complicated operations that still require statistical DOE approaches prevent us from applying the true principles of QbD to our simpler unit operations.
Wednesday, June 3, 2009
Ten Steps to Choosing your Contract Manufacturer
For many young companies, choosing a contract manufacturer, or CMO, for their lead pharmaceutical candidate is critical. Choose the wrong contractor, and you could be faced with delays and cost overruns with which your investors and patients won’t be very sympathetic. While there is no guarantee that you will always make the right decision, here are some tips that can help you make your choice in an organized, thoughtful, meaningful and objective way:
1) Make a list of all the possible suppliers. Such lists may be purchased, but they are also easily assembled from internet searches. In fact, you can do a little pre-screening with your own internet search.
2) Screen potential suppliers with a phone call. You will probably speak with a business development or sales person representing the contractor, but usually these people are quite knowledgeable about their company’s capabilities, and common problems encountered in the industry. We recommend you not reveal too many details about your project, and be prepared mostly to listen. However, you should have three or four key capabilities or proficiencies that you are looking for in all of the potential vendors. If possible, try to rule out vendors who do not meet your “must-have” requirements at this stage. Stay tuned for a blog on how to establish your showstopper list, it’s a critical exercise, and may extend beyond key capabilities and proficiencies.
3) Keep a matrix, and record the date you first contacted the vendor, when they responded to you, the status of any confidentiality agreements, and all the contact information that you can gather (email addresses, cell phone numbers, main switchboards and extension numbers). Also note the responses that each contact had relative to your three or four show-stopper criteria.
4) Meet with your team, and select three to five potential vendors to request a proposal from. We don’t recommend more than five: getting good, comparable proposals is a lot of work, like 2n times the work, where n = the number of proposers. Not to mention the work that contract manufacturers go through to read your RFP and prepare a proposal. Your three or four showstopper criteria should help you limit the number of proposers; if necessary you can begin to narrow down based on “nice-to-have” criteria as well. You may also deliberately choose to look at a range of vendors that represent different strengths/weaknesses (for example, do you prefer a “one-stop shop” that is convenient, but maybe not the best at everything, or a “specialty” vendor that provides higher levels of expertise, but will require you to select and manage multiple vendors?).
5) Solicit proposals. Most contract manufacturing seekers have a Request for Proposals (RFP) process that includes a document. These RFP documents vary from one page requirements descriptions, to lengthy, legalistic documents that require a team, and a month, to respond to. You should do what is comfortable for your organization. There needs to be enough information so that the vendor is able to respond with a meaningful proposal. There is some legal danger, particularly with intellectual property, so it’s not a bad idea to get your RFP reviewed by your legal counsel. And you should only send an RFP to a vendor after they have signed a mutually agreed confidentiality agreement.
6) Score your proposals. Find some basis to make apples to apples comparisons. RMC uses a modified Kepner Tregoe analysis, but many forms of analysis will work. You should have determined how you will assess and weight qualitative data before you begin. And in doing so, you should not under-estimate intangible factors: the ability to communicate, time zone differences, good references (you’ve checked, right?) are some examples. At this stage you should be ranking and scoring on “nice-to-have” criteria as well as comparing cost/timeline, capabilities, capacity, and viability of the business. You might form your opinion of the viability of the business by reading annual reports and press releases, and by assessing how busy the manufacturing area and support labs look during your visit.
7) Visit the top two or three vendors in person. Vendors may not allow a formal quality audit prior to signing a contract, but be sure to bring your quality representatives even for an informal “technical visit”. If the project is large, you may take the resistance to a pre-use quality audit as a red flag. Again, spend as much time as possible listening, rather than talking. Get a tour, and copies of all presentations. Ensure that you have a meeting between the decision makers for both sides as well as aligning discussions between key technical and quality personnel. If there are disputes or further work to do, your decision makers must have a good working relationship.
Your visit is also your best opportunity to break past the business development group and take a true measure of the business. Chat with the people in the lab or production area if you can. Look over the state of the equipment, the cleanliness of the facility and the stock in the warehouse. Check their flexibility-- what can they make happen for you, vs. what will have to be run past someone in another building, or another city? Ultimately, you should think about hiring a contract manufacturer similarly to how you hire an employee, by hiring for expertise as well as fit with your team.
8) Consider entering contract negotiations with at least two vendors. Things can go wrong in negotiations, and your position is stronger if you can legitimately walk away. We typically don’t let any of the final three candidates off the hook until the ink is dry on the final contract. If your budget can justify it, having a second contractor performing development work and verifying the primary contractor’s results is an excellent idea. It may ultimately spread your risk in supply chain, and give you leverage in negotiating commercial supply agreements later on.
9) Revisit your analysis tool. You may learn new things in your contract negotiations that cause you to adjust your evaluation. Don’t be afraid to be frank if you feel like terms have been changed since the selection was made. This is a good reason to keep a back up vendor.
10) You must now manage the project according to the criteria by which you selected your supplier. Hold your supplier and yourself accountable to these criteria. For example, after selecting a vendor because they can meet a very aggressive timeline, do not put the project timeline at risk by failing to order back up critical path supplies, in case the primary order doesn’t arrive, or fails to meet specifications on arrival. We will have more to say about managing a contract manufacturer in a future blog.
Choosing the right manufacturing partner is critical for your success as a drug developer. Spend the time required to make a good decision. This time should be spent gleaning as much tangible and non-tangible information on all your options as possible, and then objectively comparing it. You should have an idea about how you’re going to evaluate and weight non-tangible factors into your decision. And once you have made the choice, manage according to your criteria. Although everyone has their own methods for vendor selection, these are some suggestions that have worked well for us and our clients. If you have questions or comments, please visit http://www.rmcpharma.com/ or email us at info@rmcpharma.com.
1) Make a list of all the possible suppliers. Such lists may be purchased, but they are also easily assembled from internet searches. In fact, you can do a little pre-screening with your own internet search.
2) Screen potential suppliers with a phone call. You will probably speak with a business development or sales person representing the contractor, but usually these people are quite knowledgeable about their company’s capabilities, and common problems encountered in the industry. We recommend you not reveal too many details about your project, and be prepared mostly to listen. However, you should have three or four key capabilities or proficiencies that you are looking for in all of the potential vendors. If possible, try to rule out vendors who do not meet your “must-have” requirements at this stage. Stay tuned for a blog on how to establish your showstopper list, it’s a critical exercise, and may extend beyond key capabilities and proficiencies.
3) Keep a matrix, and record the date you first contacted the vendor, when they responded to you, the status of any confidentiality agreements, and all the contact information that you can gather (email addresses, cell phone numbers, main switchboards and extension numbers). Also note the responses that each contact had relative to your three or four show-stopper criteria.
4) Meet with your team, and select three to five potential vendors to request a proposal from. We don’t recommend more than five: getting good, comparable proposals is a lot of work, like 2n times the work, where n = the number of proposers. Not to mention the work that contract manufacturers go through to read your RFP and prepare a proposal. Your three or four showstopper criteria should help you limit the number of proposers; if necessary you can begin to narrow down based on “nice-to-have” criteria as well. You may also deliberately choose to look at a range of vendors that represent different strengths/weaknesses (for example, do you prefer a “one-stop shop” that is convenient, but maybe not the best at everything, or a “specialty” vendor that provides higher levels of expertise, but will require you to select and manage multiple vendors?).
5) Solicit proposals. Most contract manufacturing seekers have a Request for Proposals (RFP) process that includes a document. These RFP documents vary from one page requirements descriptions, to lengthy, legalistic documents that require a team, and a month, to respond to. You should do what is comfortable for your organization. There needs to be enough information so that the vendor is able to respond with a meaningful proposal. There is some legal danger, particularly with intellectual property, so it’s not a bad idea to get your RFP reviewed by your legal counsel. And you should only send an RFP to a vendor after they have signed a mutually agreed confidentiality agreement.
6) Score your proposals. Find some basis to make apples to apples comparisons. RMC uses a modified Kepner Tregoe analysis, but many forms of analysis will work. You should have determined how you will assess and weight qualitative data before you begin. And in doing so, you should not under-estimate intangible factors: the ability to communicate, time zone differences, good references (you’ve checked, right?) are some examples. At this stage you should be ranking and scoring on “nice-to-have” criteria as well as comparing cost/timeline, capabilities, capacity, and viability of the business. You might form your opinion of the viability of the business by reading annual reports and press releases, and by assessing how busy the manufacturing area and support labs look during your visit.
7) Visit the top two or three vendors in person. Vendors may not allow a formal quality audit prior to signing a contract, but be sure to bring your quality representatives even for an informal “technical visit”. If the project is large, you may take the resistance to a pre-use quality audit as a red flag. Again, spend as much time as possible listening, rather than talking. Get a tour, and copies of all presentations. Ensure that you have a meeting between the decision makers for both sides as well as aligning discussions between key technical and quality personnel. If there are disputes or further work to do, your decision makers must have a good working relationship.
Your visit is also your best opportunity to break past the business development group and take a true measure of the business. Chat with the people in the lab or production area if you can. Look over the state of the equipment, the cleanliness of the facility and the stock in the warehouse. Check their flexibility-- what can they make happen for you, vs. what will have to be run past someone in another building, or another city? Ultimately, you should think about hiring a contract manufacturer similarly to how you hire an employee, by hiring for expertise as well as fit with your team.
8) Consider entering contract negotiations with at least two vendors. Things can go wrong in negotiations, and your position is stronger if you can legitimately walk away. We typically don’t let any of the final three candidates off the hook until the ink is dry on the final contract. If your budget can justify it, having a second contractor performing development work and verifying the primary contractor’s results is an excellent idea. It may ultimately spread your risk in supply chain, and give you leverage in negotiating commercial supply agreements later on.
9) Revisit your analysis tool. You may learn new things in your contract negotiations that cause you to adjust your evaluation. Don’t be afraid to be frank if you feel like terms have been changed since the selection was made. This is a good reason to keep a back up vendor.
10) You must now manage the project according to the criteria by which you selected your supplier. Hold your supplier and yourself accountable to these criteria. For example, after selecting a vendor because they can meet a very aggressive timeline, do not put the project timeline at risk by failing to order back up critical path supplies, in case the primary order doesn’t arrive, or fails to meet specifications on arrival. We will have more to say about managing a contract manufacturer in a future blog.
Choosing the right manufacturing partner is critical for your success as a drug developer. Spend the time required to make a good decision. This time should be spent gleaning as much tangible and non-tangible information on all your options as possible, and then objectively comparing it. You should have an idea about how you’re going to evaluate and weight non-tangible factors into your decision. And once you have made the choice, manage according to your criteria. Although everyone has their own methods for vendor selection, these are some suggestions that have worked well for us and our clients. If you have questions or comments, please visit http://www.rmcpharma.com/ or email us at info@rmcpharma.com.
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