Tag: OsoBio

Jun 6, 2011 – Improved methods for the development, manufacture, and administration of drugs, particularly increasingly complex biologics such as protein and peptide therapeutics, are more in demand than ever and are being met with advanced drug delivery options. Expansion of biologics in the marketplace has fostered the exploration of drug delivery methods such as prodrug delivery, and technologies such as Hot-Melt Extrusion. Product life cycle management is also driving drug delivery technologies. With fewer new drugs coming to market, pharmaceutical companies increasingly look to hold onto product revenues of existing drugs through new drug delivery options, reformulations and product line extensions (PLE), aimed at improving either safety, efficacy, patient compliance and ease of use (or all of the above)!
The latest drug delivery trends arise from the impact of current pharma and biopharma R&D. “The drug delivery market is forecasted to grow annually by about 10% until 2013,” said Sheila Dell, Ph.D., vice president of Product Innovation at Catalent Pharma Solutions. “Oral types will remain the largest drug delivery category while parenteral, inhalation and implantable systems will grow the fastest. And eventually, parenteral formulations will surpass oral dosages due to changes in the market trends in the type of molecules that are being discovered and commercialized.” Additionally, self-administered injectable devices are gaining in popularity amidst chronic diseases and the changing healthcare environment. Inhaled drug delivery formats are expanding to accommodate everything from pain medications to autoimmune disease targets and vaccines, and drug formulation strategies are taking on the challenges that lurk between API and administration.
R&D’s Impact on Drug Delivery
With the increasing complexity of drug candidates in development and shifts in drug research strategies and methodologies, how are drug delivery technologies being impacted by current pharma/biopharma R&D? According to Mike Marek, technical project manager at OSO BioPharmaceuticals Manufacturing, LLC, “It is through increased efficacy, reduced side effects, continuous dosing (sustained release) and increased compliance, among other attributes, that drug delivery technologies are impacted by current pharma/biopharma R&D. Drug companies — from start-ups to biotech to big pharma — are involved in developing novel drug delivery systems resulting in a number of approvals.” He noted that approved dosage forms range from Vivitrol (sustained release naltrexone) indicated for opioid addiction, a microsphere dosage form, to Sylatron (peginterferon-2b) and Cimzia (certolizumab pegol), both pegylated proteins providing longer plasma half life with fewer side effects.
In addition to drug delivery advances that have resulted in improved safety, efficacy, and compliance, challenges have necessitated enhanced collaboration among R&D and drug delivery from formulation to packaging. There are significant formulation challenges with how newly developed APIs are used. According to Jamie Beggs, market development manager at Celanese EVA Performance Polymers, “Limited bioavailability has plagued some of these new APIs, which are inherently less soluble in typical excipients, or there is the challenge of larger, more complicated molecules with biologics. More demand is placed on the formulation strategy, delivery systems, and ultimately, the excipients. Alternative excipients, which can be used in conjunction with novel pharmaceutical combination devices or via different routes of administration, are one way to help researchers avoid discarding promising compounds because they can’t find a way to deliver them effectively. Examples of formulation techniques helping scientists tackle the problem of poor solubility are amorphous solid solutions and dispersions. Hot-melt extrusion, one way to create a solid dispersion, is a processing method that is gaining popularity and acceptance, and it is also a technique that is highly suited for thermoplastic polymer excipients like ethylene vinyl acetate (EVA).”
The development of complex compounds affects all aspects of drug delivery and the roles of formulation and device require an increasingly collaborative effort among drug development and delivery strategies. According to Graham Reynolds, vice president of marketing and innovation at West Pharmaceutical Services, Inc., “New, sensitive biologic products are forcing the industry to deal with packaging and delivery systems much earlier in the process. The traditional container, which has historically been made of glass, has the potential to interact in a negative fashion with these products. For instance, in a vial format, glass delamination is a potential issue. In staked-needle syringe systems, there are considerations such as adhesives, tungsten and silicone oil that can cause interactions.”
The industry is seeking alternative materials in order to get around the issues associated with glass and sensitive biologics. “New materials, including break-resistant cyclic olefin polymers, such as Daikyo Crystal Zenith and unique designs, allow for easier and safer administration,” said Mr. Reynolds. “These systems are not only manufactured from a novel plastic material that reduces the risks of breakage, but the dimensional tolerances, quality standards, and freedom from materials such as silicone oil, tungsten or adhesives, help the systems provide the combined benefits of a plastic with the features necessary to contain a sensitive biopharmaceutical. This also provides significant flexibility in delivery system design, whereby device development is not constrained by the shape and dimensional variability of existing glass containers.”
Trends & Challenges
Drug delivery is playing an increasingly significant role in the quest for new product opportunities as the pharmaceutical industry faces patent and pipeline challenges. Also, growing healthcare costs are shifting in-patient treatments to the home setting. As a result, injection delivery methods are on the rise, particularly for the treatment of chronic conditions. “While oral drug delivery is still the most active in terms of deals being signed, the market has evolved over the past few years with a variety of goals now being sought beyond the more traditional oral extended/controlled release options,” noted Fidelma Callanan, senior director, marketing and communications at Elan Drug Technologies, which was recently acquired by Alkermes. These include targeted site delivery, pulsatile release (intended to deliver a burst of drug at predetermined intervals), and bioavailability enhancement strategies. Beyond oral delivery, one of the most active areas is that of depot injectable delivery. Recent notable approvals include the anti-psychotic Invega Sustenna product, which provides for once-monthly treatment option for patients.
The most effective delivery of biologics to date remains the injection route. “Because biologics are often large molecule products that do not transport well through non-injectable delivery methods, delivery devices such as auto-injectors are often the best choice for administration,” said Mr. Reynolds of West. In the injectable device realm, prefillable syringes, pen injectors, electronic patch injectors and depot injectable delivery methods are all making significant headway in the growing area of home delivery or self-administration. The growth in these home delivery systems can, in part, be attributed to increasingly prevalent illnesses like diabetes and autoimmune diseases that require self-administration of medications. While these delivery methods represent breakthroughs, they are subject to limitations. Factors such as drug volume, dosing schedules, and the symptoms the drug is treating, all come into play with each method.
Prefilled syringes (PFS) highlight the benefits and limitations of various injectable technologies, as pointed out by Mr. Reynolds of West: “Prefillable syringes can aid in patient compliance, but most are still based around conventional glass syringes. Also, newer drugs, including those with high viscosity or that need to be administered in high volume, can present administration challenges. Pen injectors and multidose cartridges, which can be used for those who have frequent needs, are limited to specific therapies such as diabetes and growth hormones. Additionally, easy-to-use auto-injector systems, which are based on prefillable syringes, provide a more convenient method for delivering drug products, especially for patients who may have dexterity or needle phobia issues. There is a growing trend in the industry toward the use of these systems.”
There is another alternative injectable method that mitigates some of the administration roadblocks encountered with the PFS and pen injector. “The electronic patch injector system, which can deliver a large dose over an extended period of time, simplifies administration by automating processes and equipment, and can move drug infusion therapies from hospital-based to home-based settings. Newer systems, such as West’s electronic patch injector, also offer significant benefits through the inclusion of electronic systems to control dose rate, volume and also provide feedback to help compliance,” said Mr. Reynolds. As devices become more and more complex, the concept of downloading information from the drug device is another growing trend. The goal is to not only improve patient compliance, but also to provide precise information about the frequency and the amount of drug delivered.
These injectable devices not only result in ease-of-use for the patient or administrator, but also potentially help manufacturers conserve costly drug product. “Biologics can be very costly and manufacturers are increasingly seeking new ways to minimize waste. PFS, with their premeasured dosage, have the potential to reduce dosing errors and increase patient compliance while potentially saving manufacturers money. Unlike single- or multi-dose vials that may require drug product overfill by as much as 30% to ensure adequate withdrawal, a PFS can virtually eliminate the need for excess overfill. An increase in PFS and delivery systems, as well as auto-injectors, is likely. Additionally, patch-injector systems, which can provide larger doses or multiple doses over a period of time, likely will experience growth, particularly in the oncology area, where lengthy administrations may move from the hospital setting to the clinical or home setting,” added Mr. Reynolds.
Inhalable Systems
In the area of respiratory drug delivery, there have been notable advances to mechanisms such as dry power inhalation (DPI), and pressurized metered dose inhalation (pMDI) systems that have piqued interest in this delivery method and expanded the playing field to include medications that treat a greater variety of illnesses. “Inhaled drug delivery is becoming quite popular as a drug delivery method today. In addition to treating simple ailments such as nasal congestion, the treatment and management of flu, pain, migraine, etc., is seeing increased acceptance with this delivery format. Also, the use of intranasal drug delivery for prophylactic vaccines is projected to grow significantly,” said Dr. Dell at Catalent Pharma Solutions.
“There is considerable interest in delivery systems that administer drugs directly into lungs. Systems such as DPI are gaining momentum. For pMDI systems, new propellants that have minimum adverse impact on environment are also increasingly being considered. Nasal sprays have been shown to be very effective for the delivery of small molecules,” said Vitthal Kulkarni, Ph.D., scientific advisor, Research & Development, DPT Laboratories. Although inhalation devices, such as pMDI and DPI delivery systems, have been associated with complex regulatory compliance and dosing issues, more advanced delivery systems are taking dose content and uniformity out of the hands of the patient.
“For inhalation, we see a continued pressure to reduce dosing variability and increase efficiency,” said Anne Roush, business development manager at 3M Drug Delivery Systems. “Our DPIs are quite efficient at deagglomerating the powder (separating the individual particles from each other) so the drug can reach the intended region of the lung for the maximum therapeutic benefit. Improvements in delivery technologies that aid patient compliance continue to be important. New inhalers now have features such as dose counters and dosing feedback mechanisms that help assure the patient that they’ve received their medication.”
Additionally, advances in inhalable drug delivery devices have impacted formulations in that these systems can expand the range of molecules that can be delivered or enable the device to be more efficient and dose sparing. “One of 3M’s DPIs, for example, doesn’t require a formulation aid such as lactose, thereby potentially eliminating a substantial amount of formulation development work and allowing more drug candidates can be considered for inhalation delivery,” noted Ms. Roush.
Formulation Strategies
Before these increasingly complex drugs reach their destination device, there exists the elaborate matter of formulation. New manufacturing technologies are emerging to resolve some of the common barriers to successful drug delivery. These drug delivery technology trends, according to Mr. Marek of OSO Bio, include prodrugs (activated in vivo, resulting in less toxicity) heat-activated liposomes for targeted drug delivery, nanoparticles, and monoclonal antibodies conjugated to toxins, immune modulators or pegylated.
Poorly soluble compounds and protein and peptide therapeutics present some of the greatest drug delivery challenges. In an effort to get drugs to reach their disease target, a variety of methods are being employed. Also, technologies such as
hot-melt extrusion and pegylation are improving outcomes. Prodrug design, aimed at optimizing drug delivery to minimize undesirable drug properties while retaining the desirable therapeutic activity, has proven an important means of improving drug efficacy. PEGylation, a process by which polyethylene glycol chains are attached to protein and peptide drugs, has helped to resolve degradation issues and improve pharmacokinetics. Also, Hot-Melt Extrusion (HME), the process of pumping materials through a die under elevated temperature into a new uniform product, represents an efficient manufacturing process and also has the potential to improve product quality and efficacy.
“Different strategies can be applied to poorly soluble drug compounds. The use of proper surfactants, combinations of surfactants, use of co-solvents, or lipids will typically improve solubility. There are also newly developed ‘solubility improving’ excipients that may help improve solubility of drug substance in the aqueous phase. Using micronized API in combination with solubilizing agents is also used to improve solubility. Other techniques to improve solubility that are useful for certain drugs include hot-melt extrusion or forming ‘eutectic mixtures’ of API with suitable excipients,” said Dr. Kulkarni of DPT.
According to Mr. Marek, “Peptides and proteins can be pegylated to provide ‘stealth’ properties in order to increase serum half life. Proteins and peptides can also be conjugated to monoclonal antibodies for targeted drug delivery. Additionally, ‘nanotechnology’ — incorporating drugs, proteins and peptides into nanospheres — will likely have an increasing role in drug delivery.”
Ms. Callanan of Elan Drug Technologies noted, “As a consequence of the clear trends emerging from the drug discovery process, it is expected that solubility-limited oral absorption will continue to pose a significant challenge in small-molecule drug development. Several relevant technology approaches, each capable of enhancing drug solubility, are available. They include solid amorphous dispersions, pharmaceutical co-crystals, self-emulsifying and self-microemulsifying drug delivery systems, and from Elan Drug Technologies, the NanoCrystal technology.” This technology boasts five licensed products on the market and more than $2 billion in annual in-market sales, ranking it among the successful technologies available for poorly soluble compounds.
Building on the NanoCrystal technology, EDT is now advancing a new, hybrid particle-engineering approach, called NanOsmotic technology. “The attractiveness of NanOsmotic technology,” according to Ms. Callanan, “arises from its ability to maintain a drug in its original crystalline form until biologically activated.” Following activation, a thermodynamically enhanced form of the drug is delivered and maintained for a period of time sufficient to achieve absorption. Accordingly, NanOsmotic technology offers a number of potential performance advantages over alternative technologies in the poorly water-soluble drug delivery space, noted Ms. Callanan, including enhanced bioavailability, improved chemical and physical stability, higher drug loading and the ability to achieve programmable release of drug for extended periods of time.
The increased focus to create more palatable delivery methods for patients has resulted in more convenient transdermal routes and nasal delivery. However, oral delivery continues to defy research efforts. “While delivery of proteins and peptides orally would seem like an obvious field of study for drug delivery companies, success to date has been very limited. The search for formulation approaches that are stable, bioavailable, and can be readily manufactured and acceptable to the patient, has led to major advances in development of nasal and controlled release technology. And while strides are being made in fundamental research in areas including oral delivery, transdermal delivery, pulsatile and ‘on demand’ delivery of peptides and proteins, it still remains the elusive holy grail of drug delivery,” said Ms. Callanan of EDT.
“3M’s microneedle technology is very conducive to delivery of macromolecules like proteins and peptides, achieving a similar pharmacokinetic profile to IV administration,” said Ms. Roush at 3M. “For certain drugs that require rapid onset of action, the pulsatile profile of MTS might be more effective than subcutaneous or intramuscular injection. For delivery of protein and peptide vaccines, the intradermal route has advantages because the drug is presented to the area with a rich source of immune cells. Additionally, if lung delivery is desired, DPIs may be a viable method for delivery of proteins and peptides.”
Ms. Roush also described how 3M’s MTS technology impacts formulation: “Using 3M’s MTS technology, the barrier of the stratum corneum is eliminated to enable delivery of a wider variety of molecules transdermally (eg, large molecules such as monoclonal antibodies). With solid MTS (sMTS), API is coated and dried on the microneedle, allowing one to deliver solid API through the skin. This feature of sMTS may also eliminate cold chain storage for some drugs and vaccines.”
While major advances have been made to improve drug delivery options for protein and peptide therapeutics, delivering them more and more effectively and with greater ease to patients, remains highly sought after.
Lifecycle Management
The pharmaceutical industry continues to take advantage of drug delivery technologies in its efforts to add years to product revenue streams. Although more traditional approaches are often used in order to improve the likelihood of approval, emerging drug delivery technologies are peeking the interest of drug developers. “While many approaches exist to ‘lifecycle manage’ a product, those pursued using drug delivery approaches have proven more effective than most, particularly where patient/clinical benefits are apparent. New formulation strategies have been shown to deliver the best returns on investment, proving significantly more effective than an OTC/branded generic route, repositioning, or a new indication. A Merrill Lynch industry report found that 87% of ‘switch and grow’ strategies not only sustained the value of the original franchise, but increased its sales following the switch to the improved product. A good example is Ritalin LA, developed by Elan, which grew Novartis’ methylphenidate franchise by 62% in its first year following launch,” said Ms. Callanan.
Improving safety and efficacy tops the list for companies seeking enhanced drug delivery methods for existing products. Also, more efficient drug delivery can lead to cost savings when dealing with expensive API. “One area where we are receiving strong interest from our customers is sustained or controlled release formulations,” commented Ms. Beggs of Celanese. “More specifically, our customers are
looking to create formulations that are delivered over an extended period of time via a mucosal or subcutaneous route. In some cases, they are also seeking to deliver the APIs locally at the specific site of indication versus dosing systemically. Formulators can use these techniques to create products that have improved safety and efficacy profiles through lower dosing with less variation in blood plasma API concentration.
When working with these advanced delivery methods, an emphasis must be placed on designing a formulation that adequately tailors the release profile of the API. This necessitates a strong, open relationship between excipient providers and drug/device formulators.”
“The intradermal delivery area is emerging as a potential way to obtain a desired pharmacokinetic profile with a faster onset or targeting drugs to the lymphatic system,” noted Ms. Roush of 3M. “These PK profiles are difficult to match via other routes of administration. MTS offers the potential for a faster onset of action and a reduction of injection site reactions. Intradermal delivery via MTS has shown improved bioavailability when compared to subcutaneous or intramuscular injection, which may translate to similar efficacy at a reduced dose.” If the API is expensive, comparable efficacy at a reduced dose can have real benefit to both pharmaceutical companies and patients.
Self-administration of injectable medications is a fast growing trend that will likely pick up speed as drugs advance through the pipeline, and to offset healthcare costs associated bringing treatment options for chronic illnesses from the hospital to home setting. Also, the once-insurmountable challenges around poorly soluble compounds are being met with incremental success. While protein and peptide therapeutics hold great potential in the treatment of serious diseases, improved drug delivery methods remain sought after due to their fragile nature, large size, and instability. Establishing advanced drug delivery mechanisms in this area is imperative for the future success of modern medicines.

Albuquerque, NM May 11, 2011 – OSO BioPharmaceuticals Manufacturing, LLC, has received the Pollution Prevention Award for its efforts to protect water quality in the Rio Grande River.
The honor was awarded by the Albuquerque Bernalillo County Water Utility as part of its Pollution Prevention Program (P2 Program).
The P2 Program was created in 1992 to protect Albuquerque’s water treatment plant and the Rio Grande River from harmful waste runoff. The program recognizes businesses for reducing or eliminating the creation of pollutants at their source through equipment and process modifications, reformulation or redesign of products, substitution of raw materials, and improvements in housekeeping, maintenance, training or inventory control that results in reduced waste generation.
In OsoBio’s case, the company implemented changes to its raw materials processes, which reduced wastewater by 25 percent. The company also installed a state-of-the-art treatment system that improved the quality of water discharged from its facilities.
“OsoBio prides itself on being a conscientious corporate citizen in Albuquerque, which includes respecting the sensitive environment we share with our neighbors and doing our part to protect it from further degradation,” said Dr. Stuart Rose, president and CEO. “It is gratifying to know that by reducing OsoBio’s environmental footprint, we are making a positive contribution to our community.”

Mar 07, 2011 – No doubt that the Risk-MaPP approach is state-of-the-art thinking when it comes to managing the risk of cross-contamination. David Cockburn of the EMA declared as much at the launch of the new Baseline Guide in Washington, DC this past October. Although the EMA has some minor issues with the document, Mr. Cockburn acknowledged the International Society for Pharmaceutical Engineering (ISPE) for its efforts in translating a 2005 EMEA concept paper dealing with the need for updated GMP guidance concerning Dedicated Manufacturing Facilities in the Manufacture of Certain Medicinal Products into a practical reality.
ISPE recently launched its new Baseline Guide, Risk-Based Manufacture of Pharmaceutical Products, A Guide to Managing Risks Associated with Cross-Contamination (Risk-MaPP), in Europe and the U.S. both to acclaim and tough criticism. Hard questions indicated areas for improvement and areas that need further education and explanation. Let’s explore some of the questions and issues raised during the first two launch sessions.
Health-Based Limits
The cornerstone of the Risk-MaPP document is the use of health-based limits, which are referenced as the acceptable daily exposure (ADE) to determine cleaning limits, cross-contamination limits and acceptable risk. The ADE is defined as the dose that is unlikely to cause an adverse effect if an individual is exposed by any route, at or below this dose every day for a lifetime. By the definition, the risk would be acceptable if the results of cleaning data and cross-contamination data indicated levels below the ADE.
One attendee felt the ADE was too conservative because it assumes that an individual would be exposed to the cross-contamination for a lifetime. This really isn’t feasible because a batch produces a finite amount of product. Other attendees disagreed because the root cause of the cross-contamination could be a systemic issue and not a batch only issue. In addition, the product receiving the ADE amount or lower of another product could be a drug that is taken daily for a lifetime such as insulin-lowering drugs or blood pressure medicines.
This dialogue is important because it does show that the development of the ADE includes some conservatism and that adding additional safety factors to cleaning limits, etc., without justification does not protect the patient any better and may cause manufacturers to employ more costly measures to meet the newly lowered limits. The guide discusses how route adjustments can be made to cleaning limits when there is appropriate scientific justification.
During the launch sessions the EMA indicated that updated wording for the revisions to the EU GMP clauses 3.6, 5.18 and 5.19 with regards to cross-contamination and the need for dedicated facilities may be available soon. The EMA is clear that input from toxicologists is required when using risk assessments to confirm that use of multi-product facilities is safe. They are currently debating the use of a toxicological tool to determine the health-based limits. While the ADE approach is outlined in Risk-MaPP and ICH Q3C outlines the PDE method for residual solvents, the EMA is considering providing a more prescriptive tool based on either of these methods that eliminates any room for interpretation. Specifically the EMA is considering dictating the use of safety (uncertainty) factors to eliminate the variability in the limits established by different toxicologists.
The danger in having the EMA dictate the safety factors is that manufacturers could bypass the toxicological input, since the variables for determining the health-based limit will already have been defined, leaving no room for the incorporation of the professional judgment of the toxicologist. This will perpetuate the status quo, where the cleaning validation department sets the limits without discussing the hazards with a toxicologist and not allowing the proper professionals to interpret the data and assist in the risk assessment and limit-setting activities. Ideally, if you allow the toxicologists to participate and use their professional knowledge, a better understanding of the compounds and the hazards will proliferate throughout the organization rather than leaving individuals to calculate formulas without truly understanding the impact of their actions.
Cleaning
As stated above, Risk-MaPP suggests using ADE values to determine cleaning limits. In essence the ADE value would replace the 1/1000th of a low clinical dose (LCD) or the 10 ppm in rinse water to calculate cleaning limits.
Change can be difficult and some attendees defended the use of 1/1000th of the LCD and the 10 ppm models. It is important to remember that these traditional methods may be over- or under-protective of patient health. To illustrate the point refer to the tablebelow. The first three compounds have the same lowest therapeutic dose at 1 mg but have varying levels of teratogenic activity. Using the 1/1000th of the LCD or 10 ppm to set cleaning limits does not address these varying teratogenic effects, whereas using the ADE method takes these effects into consideration, as can be seen in the table. The fourth compound in the table actually has a higher lowest therapeutic dose and therefore the cleaning limits based on the 1/1000th of the LCD would also be correspondingly higher. The compound is of much more concern due to the teratogenic effects that appear at a lower dosage. The ADE derived using the teratogenic effects as the critical effect is 10 times lower than 1/1000th of the LCD. In this case, using 1/1000th of the LCD to set the cleaning limits would not be adequately protective of patient health.
So to summarize this point, unless the health-based limits are obtained, it is unclear if the limits used are over- or under-protective of patient health.
Some manufacturers may select cleaning limits based on the lowest of the values obtained by using the ADE, 1/1000th of the LCD or 10 ppm methods, which is conservative and protective of patient health. But these manufacturers are losing the opportunity to be green and cost effective. It has been established that using the ADE to determine cleaning limits is safe and that setting the limits lower doesn’t provide additional safety to the patient. But this practice may drive the company to dedicated or disposable parts/equipment, to more rigorous cleaning than necessary, or even to more cleaning failures. To be clear, the guide is not advocating that manufacturers should clean just enough to pass the limits; this is where the safety threshold value (STV) concept is important (see below).
Another important distinction is that Risk-MaPP replaces the maximum allowable carryover (MAC) term with the STV. The reasoning for this change is twofold:
First, the STV is just that: a safety threshold. If your data shows you have exceeded the STV, your product is adulterated and cannot be sold. The MAC term has erroneously led some to believe that it is “acceptable” to carry over large amounts of a compound into the next process so long as the amount is at or below the calculated value. Some may believe that they can also carry over amounts up to the STV value, even when the value is quite large. Obviously this is not acceptable. This is where the GMP requirement for visually clean equipment surfaces plays an important role. As reinforced in the visual limits workshop at the launch sessions, even under less than ideal conditions, the human eye can see fairly low residue concentrations (less than 1 mcg/cm2). So in situations where the health-based limits are high, visual limits could be used to bring some sensibility to assessment of the amount that could be carried over to the next product.
Second it is necessary to know the STV so that the risk due to cleaning/retention can be quantified. This risk is quantified by determining the distance between the actual cleaning data and the calculated STV. This distance is the margin of safety the cleaning process achieves.
As cleaning data is gathered, statistical analysis should be used to set process control limits, including alert and action limits. By using a tiered limit scheme if the process starts to drift out of the normal/expected operating range, an alert can be sent so that more attention or an investigation can be given to the process with possible corrective action completed before the process exceeds the action limits or the limits that would require rejection of the product. By understanding the process capability of the cleaning process and setting the process control limits based on this capability, a manufacturer can have confidence and evidence in their ability to minimize the risk of cross-contamination due to cleaning.
Case Studies
Two case studies were presented during the launch sessions by Oso Biopharmaceuticals and élan Drug Technologies. The OsoBio case study was for a multi-product parenteral facility and the élan one was for a multi-product facility with various dosage forms. Both case studies used failure mode and effects analysis (FMEA) to thoroughly review their risk of cross-contamination, but to start they needed to get a firm handle on the compounds they process. A matrix of compounds was developed that included basic information such as product name, ADE (if known), batches processed per year, weight of the API per batch and doses per batch. This helped them determine where to focus the risk analysis efforts. When processing many compounds in a facility, it is not feasible to analyze each possible combination of compounds.
Both companies found that the matrix alone provided some valuable insight into their operations and coupled with an in-depth FMEA exercise gave the companies a thorough understanding of their products, processes and facilities. This understanding was perpetuated throughout the company via the risk assessment process. The return on the investment is now priceless, as staff truly understand why something is done a certain way and compliance to the procedures is improved. In addition, with a better understanding, better and quicker decisions can be made.
Quality Systems and the Product Lifecycle
Although Risk-MaPP mirrors the ICH Q9 document, aspects are also inline with both ICH Q8 and Q10. Two presentations were provided that discussed how Risk-MaPP principles can apply to the product lifecycle and be incorporated into the company’s quality system. Q8 discusses pharmaceutical development and how that information is used to provide a better understanding of the processes and products for reviewers and inspectors. It also discusses how, with better understanding of the products and processes, a manufacturer may have greater regulatory flexibility. Clearly the approach in Risk-MaPP, amplified through the case studies, providesa greater understanding of the facilities, processes and products produced in a multi-product facility. This knowledge should help a manufacturer safely produce medicines while allowing flexibility in the manner in which cross-contamination is controlled.
Q10 outlines a model for a pharmaceutical quality system. Quality risk management is a subset of the quality system. The quality system includes policies, standards, procedures and the organizational responsibilities. In the context of Risk-MaPP, the following may apply:
1.A manufacturer should have a policy that stateswhat acceptable risk is. Acceptable risk should not be determined by the project team or vary from site to siteor from phase to phase (e.g. R&D to commercial).
2.Standards should be set for scoring of risks such asseverity, occurrence and detection and where the action points (e.g. no action required, investigate or stopimmediately) are for the levels of risk (e.g. low, mediumor high risk or risk priority number ranges).
3.Procedures can be developed for the use of riskmanagement tools.
4.Organizational responsibilities should explain who”owns” the quality risk management plan, who thestakeholders are, etc.
Producing medicines entails some level of risk. Under-standing and managing the risk is a requirement for providing safe medicines to the public. Ignorance is not an acceptable excuse; neither is “that’s how we did it before.” ISPE, as a catalyst for change, has provided the industry with a practical method to employ ICH Q9 to manage the risk of cross-contamination. Several excerpts from recent FDA warning letters or 483s indicate the FDA expects manufacturers to assess the risk of cross-contamination when using multi-product facilities. For example, this excerpt from a 2010 Warning Letter supports the principles within Risk-MaPP: “FDA encourages sound risk assessment approaches to address hazard identification, exposure consequences, and implement controls designed to prevent and detect cross-contamination. To achieve an acceptable level of risk require sound and risk-based assurance that one drug does not contaminate another drug.”
As Edwin Melendez of the FDA stated during the DC launch, this guide helps make the current practice as referenced by the “c” in the cGMPs available to all manufacturers, large and small. He also stated this approach applies not only to highly hazardous compounds, but equally to all compounds, including aspirin.

Mar 07, 2011 – No doubt that the Risk-MaPP approach is state-of-the-art thinking when it comes to managing the risk of cross-contamination. David Cockburn of the EMA declared as much at the launch of the new Baseline Guide in Washington, DC this past October. Although the EMA has some minor issues with the document, Mr. Cockburn acknowledged the International Society for Pharmaceutical Engineering (ISPE) for its efforts in translating a 2005 EMEA concept paper dealing with the need for updated GMP guidance concerning Dedicated Manufacturing Facilities in the Manufacture of Certain Medicinal Products into a practical reality.
ISPE recently launched its new Baseline Guide, Risk-Based Manufacture of Pharmaceutical Products, A Guide to Managing Risks Associated with Cross-Contamination (Risk-MaPP), in Europe and the U.S. both to acclaim and tough criticism. Hard questions indicated areas for improvement and areas that need further education and explanation. Let’s explore some of the questions and issues raised during the first two launch sessions.
Health-Based Limits
The cornerstone of the Risk-MaPP document is the use of health-based limits, which are referenced as the acceptable daily exposure (ADE) to determine cleaning limits, cross-contamination limits and acceptable risk. The ADE is defined as the dose that is unlikely to cause an adverse effect if an individual is exposed by any route, at or below this dose every day for a lifetime. By the definition, the risk would be acceptable if the results of cleaning data and cross-contamination data indicated levels below the ADE.
One attendee felt the ADE was too conservative because it assumes that an individual would be exposed to the cross-contamination for a lifetime. This really isn’t feasible because a batch produces a finite amount of product. Other attendees disagreed because the root cause of the cross-contamination could be a systemic issue and not a batch only issue. In addition, the product receiving the ADE amount or lower of another product could be a drug that is taken daily for a lifetime such as insulin-lowering drugs or blood pressure medicines.
This dialogue is important because it does show that the development of the ADE includes some conservatism and that adding additional safety factors to cleaning limits, etc., without justification does not protect the patient any better and may cause manufacturers to employ more costly measures to meet the newly lowered limits. The guide discusses how route adjustments can be made to cleaning limits when there is appropriate scientific justification.
During the launch sessions the EMA indicated that updated wording for the revisions to the EU GMP clauses 3.6, 5.18 and 5.19 with regards to cross-contamination and the need for dedicated facilities may be available soon. The EMA is clear that input from toxicologists is required when using risk assessments to confirm that use of multi-product facilities is safe. They are currently debating the use of a toxicological tool to determine the health-based limits. While the ADE approach is outlined in Risk-MaPP and ICH Q3C outlines the PDE method for residual solvents, the EMA is considering providing a more prescriptive tool based on either of these methods that eliminates any room for interpretation. Specifically the EMA is considering dictating the use of safety (uncertainty) factors to eliminate the variability in the limits established by different toxicologists.
The danger in having the EMA dictate the safety factors is that manufacturers could bypass the toxicological input, since the variables for determining the health-based limit will already have been defined, leaving no room for the incorporation of the professional judgment of the toxicologist. This will perpetuate the status quo, where the cleaning validation department sets the limits without discussing the hazards with a toxicologist and not allowing the proper professionals to interpret the data and assist in the risk assessment and limit-setting activities. Ideally, if you allow the toxicologists to participate and use their professional knowledge, a better understanding of the compounds and the hazards will proliferate throughout the organization rather than leaving individuals to calculate formulas without truly understanding the impact of their actions.
Cleaning
As stated above, Risk-MaPP suggests using ADE values to determine cleaning limits. In essence the ADE value would replace the 1/1000th of a low clinical dose (LCD) or the 10 ppm in rinse water to calculate cleaning limits.
Change can be difficult and some attendees defended the use of 1/1000th of the LCD and the 10 ppm models. It is important to remember that these traditional methods may be over- or under-protective of patient health. To illustrate the point refer to the tablebelow. The first three compounds have the same lowest therapeutic dose at 1 mg but have varying levels of teratogenic activity. Using the 1/1000th of the LCD or 10 ppm to set cleaning limits does not address these varying teratogenic effects, whereas using the ADE method takes these effects into consideration, as can be seen in the table. The fourth compound in the table actually has a higher lowest therapeutic dose and therefore the cleaning limits based on the 1/1000th of the LCD would also be correspondingly higher. The compound is of much more concern due to the teratogenic effects that appear at a lower dosage. The ADE derived using the teratogenic effects as the critical effect is 10 times lower than 1/1000th of the LCD. In this case, using 1/1000th of the LCD to set the cleaning limits would not be adequately protective of patient health.
So to summarize this point, unless the health-based limits are obtained, it is unclear if the limits used are over- or under-protective of patient health.
Some manufacturers may select cleaning limits based on the lowest of the values obtained by using the ADE, 1/1000th of the LCD or 10 ppm methods, which is conservative and protective of patient health. But these manufacturers are losing the opportunity to be green and cost effective. It has been established that using the ADE to determine cleaning limits is safe and that setting the limits lower doesn’t provide additional safety to the patient. But this practice may drive the company to dedicated or disposable parts/equipment, to more rigorous cleaning than necessary, or even to more cleaning failures. To be clear, the guide is not advocating that manufacturers should clean just enough to pass the limits; this is where the safety threshold value (STV) concept is important (see below).
Another important distinction is that Risk-MaPP replaces the maximum allowable carryover (MAC) term with the STV. The reasoning for this change is twofold:
First, the STV is just that: a safety threshold. If your data shows you have exceeded the STV, your product is adulterated and cannot be sold. The MAC term has erroneously led some to believe that it is “acceptable” to carry over large amounts of a compound into the next process so long as the amount is at or below the calculated value. Some may believe that they can also carry over amounts up to the STV value, even when the value is quite large. Obviously this is not acceptable. This is where the GMP requirement for visually clean equipment surfaces plays an important role. As reinforced in the visual limits workshop at the launch sessions, even under less than ideal conditions, the human eye can see fairly low residue concentrations (less than 1 mcg/cm2). So in situations where the health-based limits are high, visual limits could be used to bring some sensibility to assessment of the amount that could be carried over to the next product.
Second it is necessary to know the STV so that the risk due to cleaning/retention can be quantified. This risk is quantified by determining the distance between the actual cleaning data and the calculated STV. This distance is the margin of safety the cleaning process achieves.
As cleaning data is gathered, statistical analysis should be used to set process control limits, including alert and action limits. By using a tiered limit scheme if the process starts to drift out of the normal/expected operating range, an alert can be sent so that more attention or an investigation can be given to the process with possible corrective action completed before the process exceeds the action limits or the limits that would require rejection of the product. By understanding the process capability of the cleaning process and setting the process control limits based on this capability, a manufacturer can have confidence and evidence in their ability to minimize the risk of cross-contamination due to cleaning.
Case Studies
Two case studies were presented during the launch sessions by Oso Biopharmaceuticals and élan Drug Technologies. The OsoBio case study was for a multi-product parenteral facility and the élan one was for a multi-product facility with various dosage forms. Both case studies used failure mode and effects analysis (FMEA) to thoroughly review their risk of cross-contamination, but to start they needed to get a firm handle on the compounds they process. A matrix of compounds was developed that included basic information such as product name, ADE (if known), batches processed per year, weight of the API per batch and doses per batch. This helped them determine where to focus the risk analysis efforts. When processing many compounds in a facility, it is not feasible to analyze each possible combination of compounds.
Both companies found that the matrix alone provided some valuable insight into their operations and coupled with an in-depth FMEA exercise gave the companies a thorough understanding of their products, processes and facilities. This understanding was perpetuated throughout the company via the risk assessment process. The return on the investment is now priceless, as staff truly understand why something is done a certain way and compliance to the procedures is improved. In addition, with a better understanding, better and quicker decisions can be made.
Quality Systems and the Product Lifecycle
Although Risk-MaPP mirrors the ICH Q9 document, aspects are also inline with both ICH Q8 and Q10. Two presentations were provided that discussed how Risk-MaPP principles can apply to the product lifecycle and be incorporated into the company’s quality system. Q8 discusses pharmaceutical development and how that information is used to provide a better understanding of the processes and products for reviewers and inspectors. It also discusses how, with better understanding of the products and processes, a manufacturer may have greater regulatory flexibility. Clearly the approach in Risk-MaPP, amplified through the case studies, providesa greater understanding of the facilities, processes and products produced in a multi-product facility. This knowledge should help a manufacturer safely produce medicines while allowing flexibility in the manner in which cross-contamination is controlled.
Q10 outlines a model for a pharmaceutical quality system. Quality risk management is a subset of the quality system. The quality system includes policies, standards, procedures and the organizational responsibilities. In the context of Risk-MaPP, the following may apply:
1.A manufacturer should have a policy that stateswhat acceptable risk is. Acceptable risk should not be determined by the project team or vary from site to siteor from phase to phase (e.g. R&D to commercial).
2.Standards should be set for scoring of risks such asseverity, occurrence and detection and where the action points (e.g. no action required, investigate or stopimmediately) are for the levels of risk (e.g. low, mediumor high risk or risk priority number ranges).
3.Procedures can be developed for the use of riskmanagement tools.
4.Organizational responsibilities should explain who”owns” the quality risk management plan, who thestakeholders are, etc.
Producing medicines entails some level of risk. Under-standing and managing the risk is a requirement for providing safe medicines to the public. Ignorance is not an acceptable excuse; neither is “that’s how we did it before.” ISPE, as a catalyst for change, has provided the industry with a practical method to employ ICH Q9 to manage the risk of cross-contamination. Several excerpts from recent FDA warning letters or 483s indicate the FDA expects manufacturers to assess the risk of cross-contamination when using multi-product facilities. For example, this excerpt from a 2010 Warning Letter supports the principles within Risk-MaPP: “FDA encourages sound risk assessment approaches to address hazard identification, exposure consequences, and implement controls designed to prevent and detect cross-contamination. To achieve an acceptable level of risk require sound and risk-based assurance that one drug does not contaminate another drug.”
As Edwin Melendez of the FDA stated during the DC launch, this guide helps make the current practice as referenced by the “c” in the cGMPs available to all manufacturers, large and small. He also stated this approach applies not only to highly hazardous compounds, but equally to all compounds, including aspirin.

Albuquerque, NM Jan 26, 2011 – Susan Schniepp, vice president of quality at OSO BioPharmaceuticals Manufacturing, LLC, has been elected to the board of directors at the Parenteral Drug Association (PDA).
Schniepp has enjoyed a long and productive relationship with the PDA. In addition to serving on numerous committees and being a featured speaker at events, she received the PDA’s Distinguished Author Award for her book, Understanding the United States Pharmacopeia and the National Formulary: Demystifying the Standards-Setting Process.
Schniepp also received the PDA’s Distinguished Service Award in 2008 and its Gordon Personeus Award in 2010, which honors a long–time member for noteworthy contributions to the organization.
“Sue is a shining star within our industry for her unflagging commitment to high quality and her willingness to share her knowledge and experience with others,” said Stuart Rose, president and CEO of OsoBio. “Serving on the PDA board affords Susan yet another opportunity to spread the quality message and lead by example.”
In managing all operational quality–related issues for OsoBio, Schniepp is responsible for cGMP compliance of facilities. Quality–related matters concerning validation as well as regulatory affairs, records and filings also fall under her scope of responsibility.
Recently, Schniepp served as chairwoman of the Monograph Development–Psychiatrics and Psychoactives Expert Committee for United States Pharmacopeia (USP), a non–governmental, official public standards–setting authority for prescription and over–the–counter medicines and other health–care products manufactured or sold in the United States. USP standards for quality, purity, strength and consistency are recognized and used in more than 130 countries.
As the first woman appointed to serve on the editorial advisory board of Pharmaceutical Technology magazine, Schniepp writes the publication’s quarterly column, “Inside Standards.”
Schniepp’s term on the PDA board of directors is for two years.
PDA was founded in 1946 by a small group of pharmaceutical manufacturers who recognized the need to disseminate technical information within the industry. Today, with more than 10,000 members worldwide, PDA is the recognized authoritative voice and leading technical organization in the field of parenteral science and technology.
OSO BioPharmaceuticals Manufacturing, LLC, is a contract manufacturing organization (CMO) focusing on biologic and pharmaceutical injectables. Headquartered in Albuquerque, N.M., OsoBio specializes in products requiring complex handling, including highly potent compounds. Responsiveness, attention to detail and clear communication are the hallmarks of our client care.

Albuquerque, NM Jan 19, 2011 – OSO BioPharmaceuticals Manufacturing, LLC, has named Craig Mastenbaum director of new business development for its West Coast market.
Mastenbaum brings to OsoBio more than 30 years of leadership experience in clinical and contract liquid, lyophilized, ampule and syringe product manufacturing. Most recently, he was senior director for clinical and contract manufacturing for Dendreon Corp., a biotechnology company that develops anti-cancer agents.
“Craig has personally directed both the in-house and outsourced manufacturing of complex, sterile liquid pharmaceutical products and been responsible for ensuring key performance and quality assurance indicators,” said Milton Boyer, vice president of business development and sales. “He understands exactly what clients are looking for and how OsoBio can best meet their needs.”
Previously, Mastenbaum served as vice president of manufacturing and business development at Hollister-Stier Laboratories, where he quadrupled contract revenues, and as director of parenteral operations at Chiron Corp. He holds a bachelor’s of arts degree in microbiology from Rutgers University and a master’s degree in business administration from Gonzaga University.

Albuquerque, NM Sep 28, 2010 – OSO BioPharmaceuticals Manufacturing, LLC, has named Susan Schniepp as vice president of quality.
In managing all operational quality–related issues, Schniepp is responsible for cGMP compliance of OsoBio’s facility. Quality–related matters concerning validation as well as regulatory affairs, records and filings also fall under her scope of responsibility.
Schniepp brings to OsoBio more than 30 years of professional experience managing quality assurance within the pharmaceutical industry.
Recently, Schniepp served as chairwoman of the Monograph Development–Psychiatrics and Psychoactives Expert Committee for United States Pharmacopeia (USP), a non–governmental, official public standards–setting authority for prescription and over–the–counter medicines and other health–care products manufactured or sold in the United States. USP standards for quality, purity, strength and consistency are recognized and used in more than 130 countries.
“Sue is so highly regarded for her expertise in pharmaceutical quality that industry leaders frequently seek out her knowledge and leadership for the benefit of the general public,” said Stuart Rose, president and CEO of OsoBio. “Sue is a great addition to the OsoBio team and an asset to the clients we serve.”
Prior to joining OsoBio, Schniepp worked in quality affairs at Abbott Labs, Antisoma PLC, Hospira and Javelin Pharmaceuticals Inc.
Schniepp is an active member of the Parenteral Drug Association (PDA), for which she has served on numerous committees and been a featured speaker at events. She received the PDA’s Distinguished Author Award for her book, Understanding the United States Pharmacopeia and the National Formulary: Demystifying the Standards–Setting Process.
Schniepp also received the PDA’s Distinguished Service Award in 2008 and its Gordon Personeus Award in 2010, which honors a long–time member for noteworthy contributions to the organization.
As the first woman appointed to serve on the editorial advisory board of Pharmaceutical Technology magazine, Schniepp writes the publication’s quarterly column, “Inside Standards.”
Schniepp holds a bachelor’s of science degree from Northern Illinois University.

Albuquerque, NM Jul 6, 2010 – An expert in product containment at OSO BioPharmaceuticals Manufacturing LLC will speak at two upcoming international conferences presenting an improved scientific approach to managing the risk of cross contamination.
Kimberly K. Ray, a senior project manager at OsoBio, will serve as a featured speaker at conferences organized by ISPE, the International Society for Pharmaceutical Engineering. With more than 25,000 members in 90 countries, ISPE is the world’s largest not–for–profit association dedicated to educating pharmaceutical manufacturing professionals and advancing their industry.
Ray will speak at the ISPE Brussels Conference being held Sept. 20–23 in Brussels, Belgium, and again at the ISPE Risk–MaPP Conference in Washington, D.C., from Oct. 4–5.
The holder of a Lean Six Sigma black belt in practices designed to improve manufacturing processes and eliminate defects, Ray will discuss findings from a scientific study OsoBio recently conducted examining cross contamination. OsoBio documented that its internal quality assurance procedures are safe and effective in containing live viruses and other potentially hazardous compounds.
“There is a mindset within the pharmaceutical industry that potent compounds must be handled in separate, dedicated facilities,” said David Pittman, director of technical operations. “What we’ve done is provide scientific evidence that a multi–product–line facility like OsoBio can safely and effectively contain hard–to–handle compounds.”