When is a Kickback a Kickback?

Navigating the perilous road of marketing incentives in the pharmaceutical industry

By Ronald J. Friedman

In January 2010, the federal government filed a civil action under the False Claims Act accusing drug manufacturer Johnson & Johnson (“J&J”) of orchestrating a massive unlawful pharmaceutical monetary kickback scheme. This action by the U.S. Department of Justice serves as a reminder to all in the healthcare industry, be they pharmaceutical companies, pharmacies, medical providers or healthcare facilities, to review and examine their financial arrangements with others in order to ensure they do not contain unlawful remuneration agreements, and to be vigilant in their efforts to avoid market conduct that may be viewed by others — especially the government — as involving an unlawful kickback.

Johnson & Johnson Under Fire

The J&J case was filed as a civil action under the federal False Claim Act (Title 31 U.S.C. Sections 3729-33), seeking restitution, treble damages and civil penalties. If found liable, the action will cost J&J many millions of dollars. Omnicare, Inc., the alleged recipient of the kickback payments, has already settled with the government, agreeing to pay $98 million for participating in multiple unlawful kickback schemes, including the scheme with J&J. Omnicare is a well-established provider of pharmacy services to nursing homes and other long-term care facilities. The unlawful kickback schemes in which Omnicare is alleged to have engaged include Omnicare’s receipt of kickbacks from multiple drug manufacturers, including J&J, and unlawful kickback payments from Omnicare to multiple nursing homes Omnicare was servicing. The payments to the nursing homes were for “consultant pharmacist services” provided by Omnicare at rates below Omnicare’s cost and below fair market value, in order to induce the nursing homes to refer their patients to Omnicare for pharmacy services. In addition, Omnicare is alleged to have offered inflated prices to acquire business assets of the nursing homes as a disguised kickback for the nursing home’s utilization of Omnicare services. Civil complaints against some of these nursing homes have already been resolved with the homes agreeing to pay the government $14 million.

Criminal Unlawful Kickback Statute

While the actions against Omnicare and J&J were filed as civil actions, their liability is predicated upon alleged violation of the federal anti-kickback statute (42 U.S.C. Section 1320a-7b(b)), a criminal felony punishable by up to five years imprisonment and a $25,000 fine. While the government has at this juncture chosen to pursue the matter civilly, it should be recognized that the decision to file a matter civilly or criminally is often a matter of prosecutorial discretion and a person or business entity faces dual risks of both a civil action and criminal prosecution designed to deter such conduct. Indeed, there have been numerous criminal prosecutions in the healthcare industry for making or receiving kickbacks. Such prosecutions can be expected to increase in the future due to the healthcare reform bill (Patient and Affordable Care Act), enacted in March 2010, which lessens the burden on prosecutors by providing that the government is no longer required to prove that a defendant had knowledge of the law or specific intent to violate the anti-kickback statute.

The criminal anti-kickback statute is written in broad terms, and punishes equally those who offer to pay a kickback as well as the recipients. It also criminalizes the conduct of anyone who aids or facilitates the commission of the kickback scheme. The criminal statute makes it a crime to pay, or offer to pay, any remuneration — direct or indirect, overtly or covertly, in cash or in kind — to another person or entity in order to “induce” that person or entity to refer persons for services to be rendered under a federal healthcare program, such as Medicaid and Medicare, or to “induce” such person or entity to purchase, or to recommend the purchase of, a service or product funded by a federal healthcare program. In addition to the criminal fine and imprisonment, culpable individuals and entities are subject to civil fines of $50,000 per violation and three times the amount of unlawful remuneration paid. Offending individuals and businesses also face exclusion from further participation in federal healthcare programs.

Be Careful What You Write

In the J&J case, the government alleges J&J violated the kickback statute numerous times by entering into written agreements with Omnicare through which J&J agreed to pay Omnicare quarterly “rebates” in return for Omnicare recommending, promoting and selling various J&J drugs to nursing homes, including the anti-psychotic drug Risperdal and antibiotic Levaquin. In making its allegations, the government relies upon written documents obtained from J&J and Omnicare, including numerous e-mails written by company insiders discussing the pecuniary motives for the financial arrangements between J&J and its customer, Omnicare. While the written agreements utilized marketing-incentive language, characterizing the payments as payments for Omnicare’s “Active Intervention Program” and “Appropriate Utilization Program,” the government contends that these were merely disguised words for what were ordinary kickbacks in return for Omnicare recommending and selling J&J products. In addition, the complaint alleges J&J violated the kickback statute by making payments to Omnicare allegedly for the purchase of Omnicare “data” consisting of the names of physicians who could prescribe J&J drugs but were, in essence, rebates for recommending its drugs. Often times, according to the complaint, J&J never bothered to collect the data or was already receiving it for free. Finally, the government alleges that J&J paid disguised kickbacks through “grants,” “education funding” and “meeting sponsorship fees” to Omnicare as a subterfuge for rebates with the purpose of inducing Omnicare to recommend J&J drugs, which ended up costing the government millions of dollars in claims upon federal programs.

An Endless Variety of Kickbacks

Conduct that has been deemed to violate the anti-kickback statute includes consulting fee agreements between pharmaceutical companies and physician groups designed to induce medical providers to prescribe the company’s drugs, providing free drugs in order to induce providers to prescribe drugs or encourage the recipient providers to bill Medicaid for the samples or even to sell the samples, and providing weekend retreats, conference attendance fees, lavish meals, free rental space and other benefits in order to induce prescribers to prescribe drugs. Further, these cases reflect a willingness by the government to examine the internal documents of a company and its customers in order to see through any alleged justification for a financial arrangement and conclude that the true purpose of the arrangement is the unlawful remuneration for referring, recommending or selling drugs and services. Such investigations can be expected to continue as government and policy-makers pay close attention to the profits being earned by drug companies, pharmacies, medical providers, and healthcare facilities, and the concomitant costs being incurred by the Medicare and Medicaid programs. While there are certain “safe harbor” provisions for remunerative arrangements, set forth in the anti-kickback statute (42 U.S.C. Section 1320a-7b(b)(3)) and by federal regulation (42 C.F.R Part 1001), that offer protection for certain types of financial arrangements, these “safe harbor” exceptions are narrowly circumscribed and must be strictly adhered to in order to avoid having the arrangement considered a violation of the anti-kickback statute.

Compliance Instruction

In 2003, the Office of Inspector General (“OIG”) of the U.S. Department of Health and Human Services released its Compliance Program Guidance for Pharmaceutical Manufacturers, designed to assist pharmaceutical companies in avoiding financial arrangements amounting to kickbacks. The Guidance directs that nothing of value should be offered or provided by a pharmaceutical company under conditions that would tend to influence a provider’s prescribing practices. This Guidance is reflective of the view that the only proper consideration by a provider in deciding whether to prescribe a drug should be the effective care of the patient, not any financial consideration, direct or indirect, the provider receives as a result of prescribing the product.

The OIG has passed similar Compliance Program Guidance for Nursing Facilities and Physicians, and American Medical Association guidelines specifically counsel healthcare professionals to reject gifts and benefits from drug manufacturers and care facilities other than those of “nominal value and those with direct educational or patient benefit.” Plainly, the concern is that the judgment or prescriptive pattern of the medical care professional will be impacted by the receipt of benefits, and the federal government will be left paying the bill for this impact.

Assessing Marketplace Arrangements

While it is difficult to generalize or comment upon a financial arrangement without direct reference to it, those arrangements apt to draw the most scrutiny from regulatory authorities are any business arrangements between persons and entities in the healthcare marketplace that have the tendency to skew or weight prescribing decisions made by practitioners with no corresponding benefit to patient care, as well as those arrangements that appear to be increasing the costs of federal healthcare benefits programs due to the volume of drugs or services ordered. This is when the collective antennae of regulatory authorities tend to perk up, and one needs to ensure that such arrangements do not violate the statute or that they fit within a recognized “safe harbor” exception. For example, any rebates or price discounts by drug manufacturers need to fit with the “safe harbor” for group purchasing organizations, managed care and risk-sharing arrangements, or some other legally authorized mechanism.

Moreover, it is not always the drug manufacturer or pharmaceutical company that is promoting the unlawful kickback. There are repeated instances where it has been the physicians and physician groups that were leading the way to extract from the pharmaceutical companies and medical device makers remuneration for promoting and prescribing their products. Nevertheless, there has been ample misconduct on the part of pharmaceutical companies involving kickbacks within the last few years.

Pharmaceutical Company Misconduct

• In April 2007, Pharmacia & Upjohn Company, Inc. (acquired by Pfizer in 2003) pleaded guilty to violating the anti-kickback statute and paid more than $19 million to the government for paying a distribution company an excess payment to recommend sale of its human growth hormone drug, Gentropin.
• In February 2008, Merck and Co. paid more than $399 million to the government to resolve allegations that it violated the anti-kickback statute by making payments to physicians to recommend its drugs, disguising such payments as “training,” “consultation” and “market research” fees.
• In September 2009, Biovail Pharmaceuticals pleaded guilty to kickback charges and was fined $22 million for paying medical providers to prescribe its drug, Cardizem.
• In September 2009, Pfizer paid more than $48 million to the government to settle a variety of claims, including allegations of illegal kickbacks to providers to purchase its various drugs.
• And in March 2010, Alpharma paid more than $42 million to settle kickback allegations involving inducements paid to physicians to prescribe its morphine-based drug Kadian.

Multiple complaints against additional pharmaceutical companies alleging unlawful kickback schemes are currently pending.

Avoiding Trouble

As the federal government continues to search for ways to fund a national insurance program and to root out fraud and abuse in existing health benefit programs, one can expect the pharmaceutical industry will remain in the cross-hairs of regulatory authorities. Whistleblowers have achieved great success, earning millions of dollars for exposing fraud, abuse and criminal conduct by pharmaceutical companies, their executives, pharmacies, care facilities and providers. Settlements have grabbed major headlines due to their large figures, attracting even more focus upon the industry. Pressure can be expected to mount for the public accounting of all relationships between pharmaceutical companies, pharmacies, providers and care facilities under the belief that casting sunlight on such relationships will further serve to expose and deter misconduct by all involved, including the physician with the easily-induced prescription pen.

Given the prevailing winds, pharmaceutical companies and those with whom they interact — including pharmacists, providers and healthcare facilities — need to be especially vigilant to inspect and review their financial arrangements with others and examine those relationships with the same careful skepticism as will the government and other regulatory authorities should those practices be challenged as constituting unlawful kickbacks. No financial arrangement is worth paying a fine of millions of dollars, going to prison or risking the reputation of one’s company. Moreover, the question one needs to always ask is a simple one: Are one’s arrangements with vendors and customers “clean,” or do they contain veiled remuneration and inducements, either in cash or in kind, for referrals or for the recommendation of medical services or products covered by a federal healthcare program? If inducement is present, careful examination must be made to ensure such arrangement falls within a “safe harbor” established by statute and federal regulation.

In the area of research, for example the OIG has stated a preference for having the educational and research grant components of the drug manufacturing firm segregated from the marketing branches, that any research for which there was compensation be research that was truly conducted, that any payment given constitute reasonable compensation for the research, and that such research not simply be a vehicle intended to influence the marketing decisions of the pharmacy, care facility or prescriber receiving the “grant” payment.

Although certain kickback schemes are easy to understand, others are more complex and involve difficult questions as to whether a business has unlawfully crossed the line or is engaging in fair actions in a highly competitive marketplace. Often times, the answer to this question turns upon an assessment of the subjective and objective reasons for acting and the impact and intended impact of the actors. The answer to these questions may challenge traditional ways of doing business in America. Sometimes it may be the operators of the kickback schemes themselves who are most surprised to find that their conduct is deemed to be in violation of law. For this reason, it is useful to proceed cautiously and to have counsel — skilled in the review of such documents and arrangements and highly conversant in the application of the “safe harbors” — examine such relationships to ensure compliance with the law and to avoid your company being the next one in an unintended, and perhaps unforeseen, spotlight.

Money spent paying judgments depletes funds that drug companies need to effectively compete, conduct research, and innovate. It keeps pharmaceutical companies and pharmacies, as well as medical providers and healthcare facilities, from focusing on the true mission at hand: The cost-effective practice of good medicine and providing drugs needed in the treatment of medical illness and disease. It is through a sober look at all of one’s financial relationships with vendors that unwanted trouble can be avoided.

ffect of pharmaceuticals in the environment

(RADIUS IMAGES/GETTY IMAGES)

Concerns regarding the fate and effect of pharmaceuticals in the environment have been increasing following the detection of pharmaceuticals in sewage treatment plant (STP) effluents, surface waters, seawater, groundwater and even drinking water.^1,2 Monitoring studies have demonstrated that drug residues in treated wastewater and surface waters are widespread,² and concerns have further strengthened after residues of the analgesic and anti-inflammatory drug substance diclofenac were held responsible for the unusually high death rate among three species of vulture in India and Pakistan in 2004.³ In response, regulatory agencies have issued detailed guidance on how pharmaceuticals should be assessed for possible adverse effects in the environment and have introduced the requirement for a environmental risk assessment (ERA). An ERA is required for all new marketing authorisation applications for a medicinal product; for type II variations, an ERA should be submitted if there is an increase in environmental exposure; for type IA/IB variations and renewal applications, an ERA is not required. An assessment of potential risks to the environment of medicinal products is a step-wise, phased procedure that may be terminated when sufficient information/data is available to either indicate that the medicinal product is unlikely to pose a risk to the environment, or to identify and sufficiently characterise the potential risks.

An ERA was first required for veterinary pharmaceuticals in accordance with EU Directive 92/18/EEC and the corresponding note for guidance was issued by the European Medicines Agency (EMA) in 1998. In 2001, the requirement for an ERA was described for human pharmaceuticals in Directive 2001/83/EC. A guidance document was first issued in January 2005 (first draft) and finalised in June 2006.⁴ In comparison, in the US ERAs for veterinary and human pharmaceuticals have been required by the FDA since 1980 and 1998, respectively.

This article will describe the ERA for human pharmaceuticals in Europe and will present the steps to be taken during the phased procedure of assessing environmental risk.

Background

The main route of entry of human pharmaceuticals into the environment is through uptake in the patient followed by excretion and disposal via wastewater. Hospital wastewater, wastewater from manufacturing sites and landfill leachates may also contain significant concentrations of pharmaceuticals.¹ Pharmaceuticals that are not degraded or bound in the sewage treatment plant are released in treatment effluents, subsequently contaminating surface water and possibly ground water. Pharmaceuticals that bind to sewage sludge may also end up in the environment when sludge is spread on land, after which soil, groundwater and surface water may be contaminated.

Existing literature about the ecotoxicological effects of human pharmaceuticals deals predominantly with acute toxicity in standardised tests with aquatic organisms; however, because of continuous, low level exposure, chronic effects are considered more relevant. Therefore, the guidance for environmental risk assessment prepared by the EMA contains the requirement of chronic ecotoxicity studies.⁴

ERA: guidance

The guidance document on environmental risk assessment contains the data requirements that should be fulfilled in an ERA,⁴ but the specific data requirements are not as straightforward as they seem because the choice of the appropriate test is subject to expert judgement. Moreover, certain types of chemicals are, in principle, exempt (e.g., electrolytes, vitamins, amino acids, peptides, proteins, carbohydrates and lipids, vaccines and herbal medicinal products), but these exemptions may be overruled by the specific mode of action (e.g., when the substance has an intended endocrine mode of action).

An ERA consists of two phases: Phase I, which is a screening phase, and Phase II, which may be triggered by the results of Phase I, and in turn consists of two tiers. Phase I is generally thought to be a nontesting phase (with testing taking place in Phase II), but this is not necessarily the case. The non-testing data collected in Phase I include a calculation of the predicted environmental concentration in surface water (PEC_surfacewater) of the active substance (based on the maximum daily dose), as well as an assessment of the mode of action and observations extracted from the toxicology database on the active substance. In addition, the logPow of the active substance should be made available. If the logPow value passes the trigger value of 4.5, an assessment is needed to determine whether the substance is Persistent, Bioaccumulative and Toxic (PBT); this is where testing may be necessary. The different steps taken in Phase I and the considered triggers are outlined below.

Phase I

PEC_surfacewater calculation

A predicted environmental concentration in surface water (PEC_surfacewater) of ≥0.01 μg/L triggers a Phase II assessment. Calculation of the PEC_surfacewater is based on the maximum daily dose and uses a default market penetration factor of 1%. This factor may be refined when epidemiological data are available (i.e., prevalence of the indication), but authorities will only accept such refinement under the assumption that the new drug product will have a 100% market share; however, this is not described in the guidance.

Potential concerns at levels <0.01>

If the PEC_surfacewater is below 0.01 μg/L, no further requirements apply (in principle) unless concern exists for environmental effects at concentrations below the trigger value of 0.01 μg/L. This, for instance, is the case for highly lipophilic compounds, which may accumulate via the food chain, and endocrine active substances, which in the ng/L concentration range may affect fish reproduction.

The mode of action of the active substance should be considered to identify potential concerns. Furthermore, any data from the toxicological database demonstrating that population relevant parameters, such as growth, reproduction and survival, may be affected at low concentrations should be addressed. This assessment should be performed with caution because the receptors and physiology of mammals and aquatic (in)vertebrates may differ substantially. Consequently, the mode of action of the pharmaceutical, which was designed for mammalian physiology, may differ in aquatic (in)vertebrates.^1–2,5 If any specific concerns exist, as is evident for endocrine active substances, the standard test requirements listed in Phase II may not apply per se — a tailored strategy should be considered in such a case. A detailed description of such strategy goes beyond the scope of the present paper and is not further elaborated here.

PBT assessment

A Persistent, Bioaccumulative and Toxic (PBT) assessment is triggered for substances with logPow >4.5. A substance is classified as a PBT substance if all three criteria (persistence, bioaccumulation and toxicity) are met. These criteria have been defined in the Technical Guidance Document⁶ and the ECHA guidance in support of REACH.⁷ It should be noted that the PBT assessment is not described as being part of the Phase II assessment, nor does it trigger a Phase II assessment. Under REACH, substances with a PBT classification are candidates for substitution, but it is not yet clear in what way medicinal products with a PBT classification are dealt with.

Phase I summary

In summary, data collected in Phase I determine if a Phase II assessment is required. This is the case if the calculated PEC_surfacewater is ≥0.01 μg/L, or if concern exists that environmental effects may occur at concentrations <0.01μg/l>

Phase II

Phase II is subdivided into two Tiers (Tier A and Tier B). Environmental fate and effects testing starts off using standardised test protocols in Tier A; Tier B may be triggered by data collected and/or generated in Tier A. Again, the logPow value should be considered; if this value is 3, a bioconcentration study in fish is triggered in Tier B.

Tier A: data requirements

Fate data generated in Tier A include the adsorption to sludge and soil, and biodegradation. If the substance is found to have an affinity to bind to sewage sludge in the STP (Koc>10000 L/kg), an environmental assessment of the substance in the terrestrial compartment is required in Tier B — unless the substance is readily biodegradable. This approach is based on the expectation that biodegradable substances are not likely to end up in the environment. If the substance is not readily biodegradable and binds to sludge, it may end up in the terrestrial environment because of the spreading of sludge on agricultural soil. Furthermore, if a substance is not readily biodegradable, a water-sediment study should be performed to study the distribution of the substance in the aquatic environment. If significant migration to the sediment compartment is demonstrated (i.e., 10% of administered amount), the effects on sedimentdwelling organisms should be studied in Tier B.

Environmental effect studies in Tier A include an algal growth inhibition test, Daphnia magna reproduction test, fish early life stage test and activated sludge respiration inhibition test. It should be noted that the fish early life stage test is unlikely to respond adequately to all pharmaceutical modes of action, and a lifecycle or partial lifecycle test in fish may be more relevant in some cases.⁵ It is recommended that the responsible authority is consulted when doubts exist.

Tier B: requirements

Environmental fate studies in Tier B may include a bioconcentration study in fish and/or degradation in soil; effects studies may include testing with terrestrial organisms such as soil microflora, earthworms, springtails and plants.

Risk assessment

Using the results from the effect studies performed in Tier A, predicted no effect concentrations (PNECs) are derived for the surface water, STP and groundwater compartments, and compared with calculated PEC values (PEC_surfacewater , PEC_groundwater). If one or more of the PEC/PNEC ratios exceeds the pre-defined trigger values (1 for surface water and groundwater compartments, and 0.1 for the STP), a Tier B assessment should be conducted. This Tier B assessment may include a refinement of the PEC values using data on, for example, excretion from humans, adsorption to sludge (Koc from Tier A) and/or a refined market penetration factor. In addition, data on transformation of the substance in the environment, such as photodegradation or data from the water-sediment study, may be used.

Outcome of the ERA

Based on the outcome of the ERA, specific arrangements to limit the impact of the pharmaceutical on the environment should be considered; for example, product labelling and the inclusion of directions for safe disposal and storage in the package leaflet for patient use. In all cases, the impact should not constitute a criterion for refusal of a marketing authorisation of human pharmaceuticals; however, it should be noted that this is not the case for veterinary pharmaceuticals, where a risk to the environment does lead to refusal of a marketing authorisation.

General considerations

Experience in ERA for human pharmaceuticals is rather limited because the guidance has only existed since 2006 and some of the aspects of the assessment remain unclear. For instance, metabolites are only briefly addressed in Phase II, but the extent to which metabolites should be considered has not been defined. Likewise, the test requirements are limited to invertebrates and fish — higher organisms, such as birds, are not addressed and this is considered as a gap in the assessment. An update of the guidance document was originally scheduled for the end 2009; however, it was decided not to update the guidance, but to instead provide a document containing frequently asked questions and answers. So far, this document has not yet been received.

D.F. de Roode is Regulatory Affairs Manager at NOTOX B.V. Tel. +31(0)73 640 67 00 Fax: +31(0)73 640 67 99 Email: daphne.de.roode@notox.nl

References

1. O.A.H. Jones, N. Voulvoulis and J.N. Lester, Environmental Technology, 22(12), 1383–1394 (2001).

2. K. Fent, A.A. Weston and D. Caminada, Aquatic Toxicology, 76(2), 122–159 (2006).

3. J.L. Oaks et al., Nature, 427(6975), 630–633 (2004).

4. European Medicines Agency, Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use (EMEA/CHMP/SWP/4447/00), June 2006. http://www.ema.europa.eu/

5. M. Crane, C. Watts and T. Boucard, Science of the Total Environment, 367(1), 23–41 (2006).

6. European Commission, Technical guidance document in support of Commission Directive 93/67/EEC on risk assessment for new notified substances and Commission Regulation (EC) No 1488/94 on risk assessment for existing substances, 2003.

7. European Chemicals Agency, Guidance on information requirements and chemical saf

The Advantages Of Co-Crystals

Dana Hoff/Getty Images

Pharmaceutical developers typically prefer their bioactive molecules to be produced and delivered to the patient in a crystalline form, primarily because of the intrinsic stability and acceptable manufacturability of crystalline materials. The vast majority of marketed APIs are molecular crystals. Such crystals are composed of molecules held together by various non-covalent forces, which makes it possible to view them as solid-state supermolecules (or supramolecules).¹ The supramolecular nature of APIs dictates that their properties are modulated by the intramolecular and intermolecular interactions, manifested as the unique molecular conformation and crystal packing. That is why collective crystal properties are different from (although closely related to) the molecular properties of their building blocks — single molecules.¹ This provides the fundamental explanation for dissimilarities, which are often considerable, in physicochemical properties among various solid state forms of a given API and also allows one to adopt the principles of supramolecular chemistry to the design of functional pharmaceutical materials. The growing recognition of this concept within the pharmaceutical industry is being demonstrated by a rapidly emerging class of API solids — pharmaceutical co-crystals.^2,3 This novel type of pharmaceutical material raises a number of questions that pharmaceutical manufacturers are posing to academia. A key questions is: How can we bring together two fields, crystal engineering and pharmaceutical sciences, in order to capture the advantages of pharmaceutical co-crystalline materials to enhance the clinical performance of drugs?

Pharmaceutical designer crystals a reality?

Sidebar 1: The key advantages of co-crystals as an alternative solid state form of APIs

Pharmaceutical co-crystals are broadly defined as crystalline materials comprised of an API and one or more unique co-crystal formers, which are solids at room temperature and bound together in the crystal lattice through any type or combination of non-covalent interactions, including hydrogen bonding, van der Waals forces and π-stacking. Owing to their supramolecular organisation, pharmaceutical co-crystals posses the unique feature that beneficially distinguishes them from any other solid state form — polymorphs, salts, solvates or amorphous solids. Explicitly, these multicomponent assemblies can be designed by employing crystal engineering strategies,^3,4 which opens enormous possibilities for pharmaceutical developers in terms of tailoring the physical and material properties for the target drug. The most comprehensive list of the key attributes of pharmaceutical co-crystals as a solid state form of APIs is displayed in Sidebar 1.

Figure 1

The caffeine:oxalic acid 2:1 co-crystal is an elegant example of the successful implementation of the crystal engineering strategy for enhancing the physicochemical stability of a moisture-labile API — caffeine anhydrate.⁵ This example is depicted in Figure 1, which schematically illustrates the key steps involved in a typical crystal engineering experiment.

Sidebar 2: Five things to consider during the co-crystal formers selection process

In terms of both solid-state structure and physicochemical profile, it is co-formers that bring an additional multiplicity into a co-crystalline system. Co-former selection, therefore, is an important initial step in the entire co-crystal engineering process. To increase the probability and at the same time maximise the experimental effectiveness of generating pharmaceutical co-crystalline systems, co-formers should be preliminary evaluated against a set of typical selection criteria, which are listed in Sidebar 2. It should be emphasised, however, that the presence of chemically compatible functional groups in a given system does not guarantee success of the co-crystallisation reaction. Moreover, it is not yet possible to accurately predict if a co-crystal, a eutectic mixture or simply a physical mixture, will result from any particular reaction.⁶ For this reason, experimental co-crystal screening remains the obligatory step and must be conducted under varied conditions by employing different crystallisation techniques, including solid-based and solution-based methods.

Figure 2
Overall, the examples described above demonstrate that every advantage must be sought to aid the design of an appropriate crystalline form of an API. Thus, unsurprisingly, pharmaceutical co-crystals are gradually becoming an integrated part of the solid form screening activities of pharmaceutical companies,¹³ as exemplified by the decision tree presented in Figure 2. Finally, it should be pointed out that although bioavailability studies involving pharmaceutical co-crystals are still in their infancy, the case studies reported to date show a great promise with respect to the bioavailability enhancement of poorly soluble APIs.^14–17 More importantly, these studies have demonstrated that even the co-crystals that tend to disso

Boosting pipelines and patent lifecycles

Patents have always been an imperative tool for the pharmaceutical industry so it is not surprising that intricate patent litigations are among the key issues that have triggered the shift of concerns towards material properties of APIs. Nowadays, the need of thorough investigation and optimisation of physicochemical and material properties for in vivo performance, reliable manufacture and the protection of intellectual property is well recognised in the pharmaceutical arena.

In this context, pharmaceutical co-crystals deserve special attention. Because of a large number of potential co-formers available, co-crystals represent a broad patent space and provide enormous opportunities for companies to boost their pipelines, as well as to manage patents throughout their lifecycle.

Summary and outlook

Co-crystals are rapidly emerging in the pharmaceutical arena, especially as a means of enhancing the physicochemical profiles of existing APIs. The uniqueness of pharmaceutical co-crystals as a solid state form is attributable to their susceptibility to supramolecular design. This implies that the functional properties of APIs — including solubility, physical stability and mechanical properties — can potentially be built-in during the co-crystal design. Furthermore, pharmaceutical co-crystals offer an opportunity for companies to significantly expand their intellectual property portfolios. From this perspective, the coming years are thought to be critical for bringing boost products containing pharmaceutical co-crystals to the market.

Acknowledgements

The authors thank the Finnish Cultural Foundation and the Academy of Finland for financial support.

Inna Miroshnyk is Senior Scientist in the Pharmaceutical Materials Research Group, Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki (Finland).

Sabiruddin Mirza is Senior Scientist in the Drug Delivery and Nanotechnology Group, Centre for Drug Research, Faculty of Pharmacy, University of Helsinki (Finland).Tel. +358 9 191 59 582 sabir.mirza@helsinki.fi

References

1. G.R. Desiraju, Nature, 412(6845), 397–400 (2001).

2. O. Almarsson and M. J. Zaworotko, ChemComm, 1889–1896 (2004).

3. N. Blagden et al., Adv. Drug Deliv. Rev., 59(7), 617–630 (2007).

4. P. Vishweshwar et al., J. Pharm. Sci., 95(3), 499–516 (2006).

5. A.V. Trask et al., Crystal Growth Des., 5(6), 1013–1021 (2005).

6. N. Issa et al., Crystal Growth Des., 9(1), 442–453 (2008).

7. A.V. Trask et al., ChemComm, 890–891 (2004).

8. S. Karki et al., Mol. Pharm., 4(3) 347–354 (2007).

9. G.G. Zhang et al., J. Pharm. Sci., 96(5), 990–995 (2007).

10. A.T.M. Serajuddin, Adv. Drug Del. Rev., 59(7), 603–616 (2007).

11. J-U. A H Junghanns and R. H Müller, Int. J. Nanomedicine, 3(3), 295–309 (2008).

12. J.F. Remenar et al., J. Am. Chem. Soc., 125(28), 8456–8457(2003).

13. N. Schultheiss and A. Newman, Crystal Growth Des., 9(6), 2950–2967 (2009).

14. M.B. Hickey et al., Eur. J. Pharm. Biopharm., 67(1), 112–119 (2007).

15. D. McNamara et al., Pharm. Res., 23(8), 1888–1897 (2006).

16. N. Variankaval et al., Crystal Growth Des., 6(3), 690–700 (2006).

17. A. Bak et al., J. Pharm. Sci., 97(9), 3942–3956 (2008)

Vacuum Conveying In The Pharmaceutical Industry

Pneumatic conveying via vacuum has been used in the pharmaceutical industry for some time now. What are the newest trends in conveying of pharmaceutical powders and blends?

It is true that powder transfer via vacuum has been in use in the pharmaceutical industry for many years. Obviously, vacuum, (usually via dilute phase) has been the transfer mode of choice because of its inherent ability to keep the powder contained within the system due to the suction created by the vacuum. This is in contrast to positive pressure conveying, which is often used in other industries for high volume and long distances. Positive pressure systems have the disadvantage of possible outward leakage, particularly in cases of improperly aligned or incorrectly installed pipework.

Newer trends in conveying involve dense phase vacuum transfer for pre-blends and granulations, specialty designs for containment and cleaning, and the increased use of specially designed pneumatic receivers for refill operations for continuous pharmaceutical processes, such as continuous granulation, mixing/blending, and extrusion.

What are the differences between dense phase and dilute phase conveying?


Figure 1
Dilute phase conveying is typically used with materials where segregation or attrition in the conveying line is not a concern. Comparative gas/air velocities in a 3 inch pipe for dilute phase can range from 15.2 up to 35.6 m/sec (3000 to 7000 ft/min). In dense phase operations (Figure 1), a reduced gas velocity range of 0.4 to 8.6 m/sec (80 to 1700 ft/min) is utilised. In most applications the gas is air, however, in the pharmaceutical industry nitrogen is also widely used because of its inert nature, as well as the natural purity of the gas.

By definition, dense phase means a higher product to gas ratio, in other words a smaller amount of gas is used to move a larger quantity of product. The less gas required for transfer, the lower the power consumption of the exhauster or vacuum pump. Typically material is picked up from the outlet of a specialty hopper, which minimises the amount of air entrained in the material, and allows the slugs of product to form. In addition, the hopper also includes a type of make-up air inlet, which aids in forming the slugs as the material enters the conveying line. The combination of a relatively low air velocity and an expanded line size result in a "siphon-like" effect, transporting the material to the vacuum receiver.

The lower gas velocity used in dense phase conveying results in a much gentler action, reducing wear on the conveyed powder or granulate. This gentle action also reduces the segregation issues often experienced with the more aggressive dilute phase operation, making it ideal for the conveying of powder blends to tabletting machines or roller compactors. It should be noted, however, that there are limitations to the application of dense phase vacuum conveying; for example, conveying distances may not exceed 3.7 m (12 ft) vertical and 4.6 m (15 ft) horizontal. Also, dense phase conveying is not appropriate for conveying materials that are cohesive, hygroscopic or so coarse in particle size that they will not readily form slugs. While dilute phase vacuum conveying is fairly forgiving, dense phase is very dependent on the material characteristics; therefore it is highly advisable to perform full-scale tests when modeling a dense phase vacuum system.

How do pneumatic conveyors fit into new applications and processes involving continuous operations?

Pneumatic receivers that operate under a dilute phase vacuum transfer principle are often used as refill devices, particularly for those loss-in-weight (LIW) feeders, which are critical to continuous operations. The mode of refill of bulk material for a LIW feeder that is feeding into a continuous pharmaceutical process can be almost as critical as choosing the right feeder technology.

Figure 2

When refilling a continuous pharmaceutical process, it is imperative that the refill devices be reliable, maintaining a constant flow of either the Active Pharmaceutical Ingredient (API) or excipient to the process, and sized such that it can deliver the required amount of product within a specific refill time limit. This time limit must be short enough to allow the LIW feeder to quickly return to true gravimetric operation and ensure constant mass flow of the bulk material to the process.

In a refill operation, the pneumatic system utilizes vacuum to draw the required material into a vacuum receiver mounted over the LIW feeder on its own support structure (Figure 2). The receiver is filled to a predetermined level and then holds this material charge until the feeder below requests a refill. The level of fill in the receiver is determined by level sensors; when a refill request is received from the feeder below, the discharge valve opens and the receiver contents are discharged into the feeder hopper. At the same time, a gas pulse is sent through the filter mounted in the vacuum receiver, in order to release any material that may have settled on the filter. The filter material can vary, including options on laminated membrane-type materials, for quick release and easy clean properties.

After discharging the material into the feeder hopper below, the valve is closed again and then the receiver vacuum cycle immediately begins in order for the pneumatic receiver to be instantly ready for the next refill request. The use of pneumatic receivers as refill devices allows for an uninterrupted source of refill from bags, drums, IBC's or supersacks.

The discharge valve at the outlet of the pneumatic receiver is also critical to the refill process. The flow cutoff action of the selected valve must be quick and secure, since a slow tapering off of the refill flow needlessly lengthens refill time. Any leakage in the refill valve can cause an unavoidable, measurable weight disturbance, but will always result in a flow error in the positive direction. Butterfly valves are usually the discharge valve of choice in the pharmaceutical industry because of their easy clean design, and their availability in high containment options.

In all cases it is imperative that the overall sequencing of the product pickup process and relative sizing of both the feeder hopper and pneumatic receiver be designed in such a way as to allow for quick changeover of these pickup points without interruption of the process. For example, in cases with an IBC docking station equipped with a pneumatic pickup and a split butterfly valve, the time for changeover to a new bin can often be as much as 15 minutes. In this case, the timing of the refill sequencing and the overall feeder hopper volume must always be able to provide continuous material flow for the process, even when there is a lack of material delivery during changeover of these pick up components. Continuous system designs ensure that the overall material delivery and process feed components are tightly integrated in any continuous process, as the quality of the process is entirely dependent upon this coordinated integration.

What options and design improvements are available for cleaning pneumatic systems?

Stainless steel filter media, retractable spray balls integrated into the product pickup or vacuum receiver hoppers and specialised quick clean hopper designs are just two of the available options for pneumatic systems. For example, more recent pneumatic receivers include easy access clamp designs on the filter receiver body as well as swing away filter receiver heads. These swing away filter heads aid not only in accessibility for cleaning, but also in ease of filter removal. In addition, the use of retractable spray balls eliminates the worry of possible contamination traps that exist with internal static spray ball assemblies. With the retractable design, the spray ball is introduced into the receiver body only during the cleaning cycle, by means of a water pressure-activated spring. This design allows the end-user to wet the internals of the pneumatic system, without exposure to the operators, and create a "mud condition" with the product. This mud condition then prevents any airborne particulates and resultant dust exposure when the system is opened.

Finally, as stated earlier, filter media is available in a variety of materials of construction, depending on the cleaning requirements, material release properties, and filtration efficiencies that are required.

How are conveying systems engineered to handle potent compounds that must be contained?

In addition to the containment of dust by introducing the wash in place design on the pickup points and filter receivers, the actual product source docking stations and discharge points can be equipped with split butterfly valves for added containment.

The use of product delivery via glove box designs can also be easily integrated to include vacuum pickup hoppers for complete contained conveyance of the active powder to the vacuum receiver.

As an added component, the use of bag in bag out secondary inline filters are often used after the vacuum receiver, for the airflow which exits the receiver prior to the vacuum pump. This added filtration unit ensures no particulates bypass to the pump, especially in the case of a broken or poorly installed internal vacuum filter, thus ensuring containment of the active powder throughout the process.

Collaboration, Storytelling: Potent Potions for Pharmaceutical

By Vicki Powers

Research and development spending in the pharmaceutical industry has jumped 43% since 1995, according to the Pharmaceutical Research and Manufacturers Association of America (PhRMA), even though new drug approvals have dropped 49%. All of that contributes to an extremely competitive environment where shaving years, or even months, off the average 12- to 15-year drug product development cycle can create huge returns.

Knowledge management is critical in the pharmaceutical industry, according to Carla O'Dell, president of the Houston-based American Productivity & Quality Center, because its product is actually "bottled knowledge." The industry emerged as an early adopter of knowledge management in the mid- to late-1990s but ended up focusing too much on intellectual capital and codification, rather than knowledge transfer and collaboration. Many of those organizations backed off their KM activities for a few years, according to O'Dell, and lost ground.

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Trans Epithelial Electric Resistance (TEER) Measurements

World Precision Instruments Inc

Category: TEER Measurement | 26/04/2006 - 10:53:49

The confluence of the cellular monolayer is quickly determined by a sharp increase in TEER. Recently there has been a significant surge of interest in introducing a combined electrode for resistance measurements in the Millipore 96-well PAMPA (parallel artificial membrane permeability assay) plate.

TEER measurement technology, which was first introduced by WPI in the mid-1980's, has since been perfected and expanded to include a range of TEER related manual and automatic instrumentation.

EVOM - Epithelial Voltohmmeter

• Manual TEER measurement of epithelial cells in 24- and 96-well plates
• Battery powered electrically isolated meter
• AC current avoids adverse effects on tissue
• Compatible with Endohm chambers
• STX2 manual electrode enclosed with meter
• STX2 can be sterilized with EtO, alcohol or a bactericide

The EVOM was the first instrument designed specifically to perform routine TEER (Trans Epithelial Electric Resistance) measurement in tissue culture research.

The battery-powered EVOM produces an AC current that avoids adverse effects on tissues, which can otherwise be caused, by a DC current -- including electrode metal deposits.

The EVOM has an easy-to-read LC display and is also available with a BNC recorder output (EVOMX). Input impedance of the EVOM is greater than 1010 ohm, and resistance ranges from 0 to 1999 ohm; and 0 to 20,000 ohm can be monitored using the switchable range setting located on the instrument front panel.

One unique feature of the EVOM is that resistance readings are unaffected by membrane capacitance and membrane voltage. The membrane voltage reading range is ±200 mV. EVOM comes complete with the popular STX2 "Chopstick" electrode set. The STX2 consists of a fixed pair of double electrodes, 4 mm wide and 1 mm thick.

Each stick of the electrode pair contains a silver/silver-chloride pellet for measuring voltage and a silver electrode for passing current. The small size of each electrode is designed to facilitate placement of the electrodes into cell culture wells.

STX2 can be used with all tissue culture inserts currently on the market. For more accurate quantitative measurements and/or for lower resistance measurements (e.g., endothelial tissue cultures) the EVOM can be used in conjunction with the optional Endohm chambers.

EVOMX

• BNC output for Data Acquisition System
• Toggle switch for continuous measurement

EVOMX is a modified version of the EVOM and is recommended for use with STX100 series electrodes. Its measurement switch and circuits have been modified to remain ON continuously.

This enables the user to have one hand free to move the electrode while using the other to note the readings. A BNC recorder output connector is provided on the EVOMX to permit direct recording of TEER measurements to a chart recorder or computer-based data-acquisition system.

STX100 Electrodes

• Designed for 24-well HTS plate (Corning Costar and BD Falcon) and with 96-well plates (Millipore and BD Falcon)
• Improved accuracy down to 5 Ohm
• Sterilized with EtO, alcohol or bactericide

With the development of a High Throughput Screening (HTS) protocol for faster drug discovery, a new line of cell culture filter plates have been introduced by several major cell culture insert manufacturers.

These HTS plates normally have either 24 or 96 individual cell culture inserts "bonded" together as one plate so that it can be handled by a robot apparatus. In response to these developments, WPI has developed an automatic REMS system and a manual electrode, STX100, for TEER measurements using HTS plates.

STX100's design is based on the same reliable design principle as the universally used STX2 electrode, with several important modifications. The size of the electrode tip has been reduced to 1.5 mm to facilitate positioning through the narrower slit of the HTS plate. The STX100 electrode itself is constructed using a stronger material for higher durability and maximum usage applications. The bottom section of the electrode is shaped to fit neatly into the "keyhole" shaped filter well.

This enables the STX100 electrode to produce increased accuracy and reproducibility of TEER readings (±5Ω) compared to the standard STX2. Several versions of STX100 are available, designed to fit the Corning Costar 24-well HTS plate, the Falcon 24 well HTS plate, the Millipore Multiscreen CaCo 96-well plate, and BD Falcon HTS 96-multiwell plate. Measurement can be directly performed when the HTS plate is in either a common or divided tray, reducing the possibility of contamination as well as mechanical damage to the cultured cells.

Multi-96

• Resistance measurement with 96-well PAMPA (parallel artificial membrane permeability assay) plates

Non-cell based 96-well PAMPA assays have been designed for predictive drug candidate testing. To ensure that the donor/acceptor fluxes are not due to porous or unstable hexadecane layers, the stability of the hexadecane membrane can be tested at the end of the incubation period by electrical resistance measurements.

To conduct the measurement a PAMPA plate is transferred to MULTI-96. Like the other Endohm models (designed for individual cell culture cups), the base of MULTI-96 is a fluid- filled receptacle for the PAMPA plates, also serving as the bottom half of the electrode pair.

Inserting the top electrode into each well allows the user to obtain the resistance of the synthetic membrane layer of that well. MULTI-96 provides a stable and reproducible reading of tissue culture resistance. EVOMX is recommended for use with MULTI-96.

ENDOHM

• TEER measurement of endothelial cell cultures in individual cups
• Compatible with EVOM and EVOMX
• Improved accuracy of 1-2 Ohm
• Accommodates 6mm, 12mm, 24mm cups and Costar Snapwell cup
• Sterilized with EtO, alcohol or a bactericide

Using WPI's EVOM resistance meter, Endohm chambers provide reproducible resistance measurements of endothelial tissue in culture cups. Transfer cups from their culture wells to the Endohm chamber for measurement rather than using hand-held electrodes. The chamber and the cap each contain a pair of concentric electrodes: a voltage-sensing silver/silver chloride pellet in the center plus an annular current electrode.

The height of the top electrode can be adjusted to fit cell culture cups of different manufacture. Endohm's symmetrically apposing circular disc electrodes, situated above and beneath the membrane, allow a more uniform current density to flow across the membrane than with STX2 electrodes. The background resistance of a blank insert is reduced from 150 Ω (when using WPI's hand-held STX2 electrodes) to less than 5 Ω.

With Endohm's fixed electrode geometry, variation of readings on a given sample is reduced from 10-30 Ω with STX2 electrodes (depending on the experience of the user) to 1-2. Compared with other resistance measurement methods, Endohm with EVOM offers a much more con-venient and economic solution to "leaky tissue" measurement. Because of the uni-form density of the AC square wave current from EVOM, errors owing to electrode polarization or membrane capacitance are largely eliminated.

Endohm together with EVOM offers the most accurate and economical endothelial ohmmeter now avail-able. To date, cups from Costar, Millipore, ICN Biomedicals, and Falcon have been tested. Endohm chambers may be sterilized with EtO, alcohol or a bactericide (also see: Cidex, Microsurgery section); not autoclavable.

Automated TEER Measuring System

The REMS AutoSampler automates measurements of electrical resistance of transepithelial, transendothelial or Caco-2 cell membranes being grown to confluence on microporous filters of high throughput screening (HTS) 24- and 96-well microplates. It is a PC-controlled, tissue resistance measurement system that offers reproducibility, accuracy, flexibility and ease-of-operation for this kind of measurement.

Automated measurement of tissue resistance in cell culture microplates provides the important advantages of speed, precision, decreased opportunity for contamination and the instant availability of measured resistance data on a computer. These measurements are useful in applications such as drug bioavailability studies and studies on the mechanisms of drug transport.

The main components of the REMS AutoSampler include: the robotic sampler that moves the electrode over each well of the microplate, the electrode which is located on the robotic arm, a base plate for the 24- and 96-well tray, a Windows-based data acquisition card, the REMS interface unit and the REMS software to operate the system on a Windows-based computer.

The REMS AutoSampler automates TEER measurements previously made with WPI's EVOM Epithelial Voltohmmeter. Automated tissue resistance measurements up to 20 kΩ can be performed on 24- or 96-well HTS microplates. Microplates presently supported include the Corning Costar HTS Transwell-24, Falcon HTS Multiwell insert systems, and Millipore Multiscreen™ CaCo 96-well plate.

The REMS AutoSampler is designed to facilitate integration with other robotic systems. Special locating bars are installed on the REMS base platform that allow other system robots to place an HTS tray into a precise location on the REMS base.

The REMS AutoSampler will automatically measure and record tissue resistance from a user-specified matrix of culture wells on the microplate. According to the specified sequence, the robotic arm moves over the identified wells taking TEER measurements. By means of a x-y-z locating system, the electrode-containing arm is positioned precisely and reproducibly over each well.

The ability of the REMS AutoSampler to reproducibly and precisely locate the electrode results in highly reproducible TEER measurements. TEER measurements are stored in the computer as the electrode moves from one well to the next. The Windows-based software provides user-friendly features to acquire, display and store the tissue resistance measurements.

The REMS electrode is very compact and robust in design. Each of two rod-shaped probes, 1.5 mm in diameter, consists of a pair of electrodes: one electrode for injecting current and the other for measuring the voltage. The use of two pairs of electrodes eliminates the error caused by the electrode-liquid interface.

To take a measurement, the robot inserts one probe into the center of the filter well and the other into the opening slot of the 24- or 96-well plate. The use of AC current to measure resistance provides several advantages over DC current, including:

• Absence of offset voltages on measurements;
• There is a zero net current being passed through the membrane and therefore it is not adversely affected by a current charge;
• No electrochemical deposition of electrode metal.

The REMS AutoSampler also features a rinse and calibration check station. If occasional rinsing of the REMS electrode is required it may be sent to a rinse station by pressing the rinse station button on the menu bar. The rinse station can also function as a calibration check station when fitted with a calibration cell containing a synthetic membrane (WPI's optional CALICELL-HTSF).

The use of this calibration cell, which mimics a confluent epithelial membrane's resistance in fluid, provides a quick and effective test to determine when the REMS measurement system is fully initialized following start-up and to check its functionality during operation.

REMS Kit

• Give your HTS system the ability to perform REMS TEER measurements

WPI's REMS TEER measurement system is also available in a fully customizable package that does not include the robot. The REMS-KIT is designed to enable manufacturers and users of robotic and HTS systems to incorporate TEER measurement capability into their own automated protocols. Essentially the REMS-KIT provides the same TEER measuring system as the REMS but without the robot positioner.

Control over TEER measurement is accomplished using the DDE protocol. Virtually any Windows-compatible programming language that uses the DDE protocol (including LabView and Visual Basic) can be used.

The REMS-KIT is designed for use with Corning Costar HTS Transwell-24, Falcon HTS Multiwell Insert System and Millipore MultiscreenTM CaCo 96-well plates. The system includes the following components:

• REMS TEER electrode with 5-ft cable
• Dummy TEER electrode for training robot
• REMS TEER measurement electrode interface unit
• Windows PCI A/D data acquisition card
• Interface software using the DDE protocol
• Instruction Manual

Osmometers

Vitech Scientific - Vital Clinical Photometers

Category: Osmometry

If one of these colligative propertieschanges, all the rest change by a predictable amount. In aqueous solutions the thing that can bring about change to these colligative properties is the amount of dissolved material present. In fact the change is directly proportional to the total number of molecules and ions present, irrespective of their size and molecular weight, a large protein molecule will have the same effect as a single Na+ ion.

So one mole (the molecular weight in grams) of any substance dissolved in one kilo of water will cause an osmotic pressure of 17,000 mmHg, a Boiling Point Elevation of 0.52oC, a Vapour Pressure decrease of 0.3 mmHg and a Freezing Point Depression of –1.86oC, although it’s more usual to express this as an Osmolality of 1000 mOsmols per kilo of Water, 1000 mOsmols for short.

Some people confuse Osmolality with Osmolarity. A solution with an Osmolarity of 1000 would contain one mole of substance in one liter of Water, which will clearly be a stronger solution as it won’t contain quite as much water as the one made up with one kilo of water. For example, one mole of sugar made up to one liter will contain less water than a mole of salt made up to a liter due to the extra space taken up by the sugar molecules.

Although both solutions will have an Osmolarity of 1000 the sugar solution will have a much higher Osmolality. It’s usual to refer to Osmolality rather than Osmolarity when dealing with solutions containing mixtures of substances since comparisons can then be made between solutions of different strength irrespective of the molecular weights of the substances dissolved in them

What is the best way of measuring this? Osmotic Pressure, the pressure generated across a semi-permiable membrane with water on one side and the solution you are measuring on the other, would seem to offer the best choice with such high pressures being produced from relatively low solution strengths. In practice it is impossible to measure due to the problem of getting a perfect semi-permiable membrane, small ions will always get through.

Even if the perfect membrane did exist the pressures exerted are so immense, 23 atmospheres for 1000mOsmols, that it would be sure to burst! Of course, if you want know about only the larger molecules, such as proteins, you can measure Osmotic Pressure with a Colloid Osmometer and select an appropriate membrane with a cut-off of 10,000 or 20,000 Daltons which will hold back the protein molecules but allow everything else to get through. But this is no use if you need to know the total Osmolality.

Measuring Boiling Point Elevation is messy and the change in BP is only small, clearly this is not an option for blood samples, unless you want a blood curdling experience, so we are left with Vapour Pressure and Freezing Point Depression. Vapour Pressure works, but there is a drawback when measuring solutions containing other liquids which exert a vapour pressure of their own, for example a blood sample containing alcohol will give a misleadingly high result.

So we come to Freezing Point Depression, which doesn’t have any of the drawbacks associated with the other methods. You need to be able to measure temperate very accurately, 1 mOsmol will produce a temperature change of only 0.0018oC, but it is a robust method and the one in universal use in Clinical Chemistry Labs and Quality Control Labs throughout the World.

In practice the sample is supercooled to a predetermined temperature, lower than the expected freezing point, as shown on the Standard Freezing Curve. Freezing is initiated either by a physical shock or in some cases by seeding with a small crystal of salt or a very cold stir wire. This produces a water-ice mixture which remains at the freezing point plateau for long enough to measure the temperature, provided you have an accurate thermometer, usually a calibrated thermistor, selected to give a linear response. Freezing Point Osmometers are calibrated at two points against accurately made up salt solutions with a known freezing point and then checked with a control solution with a known value around 290 mOsmols such as Clinitrol.

What are the main applications? Well pretty well every Hospital Biochemistry Lab in the World will have one for measuring blood and urine osmolality. The body does a good job of maintaining blood at a constant osmolality of around 290 mOsmols so any departure from this can be significant. It won’t tell you what’s wrong with a patient, but taken together with other observations or tests it can assist diagnosis or enable a course of treatment to be monitored.

A raised osmolality can often occur after surgery or with severe burns patients due to evaporation and an Osmometer can not only be used to detect this but also monitor the infusion of liquids to correct it. The Kidneys concentrate urine and Renal Function can be measured by comparing serum and urine levels. A 24 water deprivation test requires hourly osmolality measurements of both. Because they are so quick and easy to use Osmometers can often be found in Intensive Care Units and Special Burns Centres for immediate use as well as in the Biochemistry Lab.

The application for quickly screening patients admitted into Casualty in a coma, for alcohol poisoning has already been mentioned. In this case a significant difference between measured and calculated osmolality, derived from measuring electrolytes and adding a bit more for glucose and urea, can point to the likelihood of alcohol being present. This is known as the “the Osmolar Gap”, although it should more correctly be referred to as “the Osmolal Gap”!

But Clinical applications aren’t the only use to which an Osmometer can be put. Recently Sports Physiologists have been using them with elite Sportsmen and women for measuring early morning urine samples as an indicator of hydration levels. Anything over 600 mOsmols indicates that more water should be drunk. If the reading is over 1000 mOsmols it is regarded as a warning not to take part in any strenuous exercise until the body has been re-hydrated. It’s actually quite dangerous to exercise whilst de-hydrated.

Another area where Osmometers are proving useful is Quality Control Labs, especially those producing solutions used for injection or cell culture, like Pharmacies and IVF Clinics, or for eye treatment, such as eye drops and contact lens wash solution, or for checking that so-called “isotonic Sports Drinks” are in fact iso tonic. In fact osmolality is often used to ensure that formulations have been made up correctly as this is usually much quicker and cheaper to do than a full chemical analysis.

Osmolality is also used to monitor the progress of fermentation processes when large molecules are broken down into smaller ones with a corresponding increase in osmolality. One advantage of Osmometers in all the above applications is that it only takes a minute to get a result and no sample preparation is necessary.

Osmometers come in all shapes and sizes. If there is not a lot of sample available, which may be the case for clinical applications, then micro Osmometers are available which work with samples as small as 20µl. If there is plenty of sample available, which is usually the case with the QC applications, then other models are available which work with larger samples of 200µl.

In summary, Osmometry is a useful analytical tool, often overlooked, because it quickly measures everything in the sample rather than a specific constituent, but vitally important if the overall solution strength is critical.

Cleanroom Validation Test Programme Report

Category: Cleanroom Validation

Method Statements describe in detail the test methods employed for that particular test programme. Every validation is different and test methods vary accordingly, so the blanket inclusion of standard operating procedures is not sufficient. Above all, the method statements must comply with appropriate standards and be capable of close scrutiny by quality personnel, auditors and the regulatory authorities.

Cleanroom Validation Report

The Validation Report describes in detail the test programme and quantifies all results and measurements. Test Reports include all the test sheets for laminar flow cabinets, safety cabinets, isolators and fume cupboards. Each sheet has been devised to cover all the requirements of the relevant standard. Airborne Particle count sheets include printouts of all the airborne particle counts taken on site.

Test Certificates certify that the room or device which was tested meets the relevant standard. The Plans section will include drawings of all the areas surveyed, showing airborne particle count positions, differential pressures and other information appropriate to the validation. Calibration Certificates are included for instruments used in the test programme.

Each page in the report is numbered consecutively and is embossed to prevent duplication. Reports are produced as soon as possible after the work is done and we are always looking for ways in which technology can speed up this process.

Valid8 UK Ltd can provide a comprehensive test and maintenance solution for virtually any clean air device or cleanroom facility. We are committed to our clients' needs and aim to be the preferred choice for cleanroom validation.
Why is the Valid8 UK Ltd validation service better?

• High calibre, professionally qualified site engineers
• Continual investment in staff training
• Concise, customised, professional test reports
• Latest test equipment
• Full engineering support service

We can validate to all international standards including ISO 14644: 1999, EEC GMP: 2002, Fed Std 209E: 1992, BS 5295:1989andIES-RP-CC006.2.

What test procedures are offered?

• Air velocity and volumetric flow rate measurement
• Room differential pressure testing
• Filter integrity leak testing (DOP method)
• Airborne particle counting
• Airflow visualisation and digital video analysis
• Construction joint integrity testing
• Recovery performance testing
• Airflow balancing
• Temperature monitoring
• Lighting levels checks
• Noise level checks
• Pressure and flow gauge calibration

Valid8 UK Ltd can also provide the following protocols to obtain MCA /FDA approvals.

• Design Qualification Protocol
• Installation Qualification Protocol
• Operation Qualification Protocol

Regular validation minimizes product defects, costly downtime & hence increases productivity. We are providing independent customer-friendly cleanroom validation service with sophisticated calibrated instruments.

Cleanroom Service includes:

1. HEPA filter Leak Testing
2. Velocity Measurement
3. Airborne Particle Counts Monitoring
4. Recovery Test
5. Air Changes Calculations
6. Air Direction / Air Flow Visualization Study & Videography.

Valid8 Uk Ltd experienced Validation Team can carry out all routine cleanroom testing, to meet the requirements of BS EN ISO 14644. Our in house team offer the service of creating the SOP's and test protocols for your facility, re-writing existing protocols to suit new demands on your facility or utilising your current site protocols.

Valid8 UK Ltd have experience in the following test procedures:

HEPA Filter Integrity Testing

The filter media and the housing will be checked to ensure that no airborne contamination passes into the cleanroom as a result of bypassing the filter installation.

Pressure Differential Tests

This test demonstrates that the airflow between areas in the cleanroom suite cascades in the correct direction and that the pressure differences are correct.

Air Velocity & Uniformity Tests

This test will demonstrate the effective unidirectional airflow for laminar flow workstations and rooms.

Air Volumes & Air Change Tests

Tests will show that the correct volume (turbulent ventilated cleanroom) or the velocity (unidirectional cleanroom) is entering the clean area. Further tests will show that the number of air changes within the area complies with the specification.

Containment Leak Tests

This test is carried out to demonstrate that airborne contamination does not enter from a higher pressure area adjacent to the cleanroom by means of leaks in the construction materials.

Airborne Particulate Counts

This test proves the classification of the area has been achieved with regards to the concentration of airborne particulate. See table below for selected ISO 14644-1 cleanroom classifications.

Clean-up & Recovery Tests

Demonstrates the ability of the room to remove particulate by purging the area with filtered air and that the room can change from a "dirty" to "clean" state within the specified time.

Airflow Visualisation and Smoke Tests

This test, usually with video evidence, will show the airflow patterns and movement within the cleanroom, to show good coverage of critical operator and / or machine areas and highlight any zones with poor air movement.

Other tests include:

• Temperature and Humidity Testing & Mapping
• Noise Tests
• Lighting Level Tests

A full comprehensive validation report will be issued to the client following each visit which will include confirmation that all testing equipment used by Valid8 UK Ltd is maintained and calibrated to national standards.

Schedule of Tests to Demonstrate Continuing Compliance
Test Parameter	Class	Maximum Time Interval	Test Procedure
Particle Count Test	A, B <= ISO 5 C, D > ISO 5	6 Months	SO 14644 -1 Annex A ISO 14644 -1 Annex A
Air Pressure Difference	All Classes	12 Months	ISO 14644 -1 Annex B5
Air Flow	All Classes	12 Months	ISO 14644 -1 Annex B4

Schedule of Additional Optional Tests
Test Parameter	Class	Maximum TimeInterval	Test Procedure
Installed Filter Leakage	All Classes	24 Months	ISO 14644-1 Annex B6
Containment Leakage	All Classes	24 Months	ISO 14644-1 Annex B4
Recovery	All Classes	24 Months	ISO 14644-1 Annex B13
Air Flow Visualisation	All Classes	24 Months	ISO 14644-1 Annex B7

Conclusion

The key to providing maximum reliability with a minimum of shutdowns is a good preventive maintenance program.The first year of a clean room maintenance contract will usually reveal the personality of a particular building in both filter and equipment frequencies.

Monitoring how dirty the pre-filters are during service, and the changes in magnehelic readings on the bag (or box) filter housings, will ultimately determine the actual frequency of the filter changes.

In addition, working closely with the occupants of the clean room, as well as the facilities personnel, will help you discover the needed frequency of the equipment maintenance.

Product Quality Reviews

Somerset House Consultants

Category: Product Quality

The incentive for this change came from a number of high-profile inspection failures and product recalls. Inspectors found that, over time, modifications had been made to manufacturing or testing procedures, specifications, equipment etc, which had not been incorporated into the regulatory approvals for the products.

The final version of the guideline was published in October 2005, and came into effect on 1 January this year. Medicines Inspectors will be looking for evidence that these reviews are being carried out and properly documented. Failure to do so will be highlighted as a deficiency in the inspection report, and could lead to action against the company and their Qualified Persons.

Companies that supply products to the USA will be used to providing Annual Product Reviews in the FDA format. The information required in the EU Product Quality Review is slightly different, so a separate document will be needed. The FDA review is intended to confirm that every batch of product released during the review period complied with the registered process and specification. The EU review concentrates on the quality systems and processes, to show that they continue to produce consistently good quality product. Inspectors will not expect to see reams of raw data, but the results of the analysis of these data and the implementation of appropriate process improvements.

The Product Quality Review can be used as part of a continuous improvement quality system to highlight where development resource can most effectively be targeted. It can:

• Decrease the risk of out-of-specification results
• Minimise the risk of rework/reprocessing
• Decrease downtime
• Increase productivity
• Decrease the risk of product recalls
• Meet all regulatory commitments/requirements
• Improve communication between production, engineering, quality and regulatory functions

The last point can be very important when activities such as production, distribution, stability testing or regulatory affairs are outsourced to other companies.

If the product is contract manufactured on behalf of the Marketing Authorisation holder, the Product Quality Review needs to be a joint activity between the MA holder and the manufacturer. In addition, the Qualified Person at the manufacturer must assess the final review document, to satisfy themselves that the process is in control, and that they can release batches for sale. This will require Technical Agreements detailing which company will be responsible for each aspect of the review, and the procedure for analysing data and producing the final document.

The review should cover the following:

Starting materials and packaging materials

Are they still being supplied by the source specified in the Marketing Authorisation? Has the specification changed, and is it appropriate to ensure the quality of the final product? Have the suppliers of active ingredients been audited to ensure that they comply with GMP? Have there been any problems with the suppliers, eg rejections of incoming batches?

Critical in-process controls and finished product results

Are these still the same as the ones in the Marketing Authorisation? Do the controls ensure that the finished product is of suitable quality? Are all test methods validated according to current standards?

Batch failures

How many batches were rejected during the review period? What investigations were carried out at the time? Were there any trends or similarities about the failures? Have any process changes been made to prevent recurrence?

Deviations and non-conformances

How many have occurred during the review period? What investigations were carried out, and what corrective and preventative actions were introduced to prevent recurrence? Were these actions effective? Was the Marketing Authorisation varied?

Changes to processes or analytical methods

Have these changes been properly authorised and validated? Has the Marketing Authorisation been varied to incorporate them? Have new or modified equipment or procedures been introduced that will require revalidation?

Marketing Authorisation variations submitted during the review period

This includes not only those that were granted, but also those refused, and those for third country (export only) dossiers. Does the Marketing Authorisation correctly reflect the manufacture and testing of the product? Why were variations refused; is more data needed?

Stability testing results

What are the results from routine stability testing of production batches? Do they still demonstrate that the product will meet the shelf-life given in the Marketing Authorisation? Are any adverse trends becoming apparent? (This may require additional statistical analysis of the results from all stability trials on the product). Are the tests and methods still appropriate for assessing the stability of the product? Do any changes to starting materials or processing methods mean that a full stability trial should be repeated?

Returns, complaints and recalls

How many of these have occurred during the review period? Were they adequately investigated, and what changes were implemented to prevent recurrence? Were these changes effective? Are there any trends to the complaints?

Adequacy of previous process or equipment corrective actions

Corrective and preventative action (CAPA) programmes will have been instituted to resolve problems arising during the review period, but did they fully achieve this? The Product Quality Review is a good time to confirm that CAPA programmes were appropriate, or to introduce further changes.

Post marketing commitments

Regulatory authorities often approve Marketing Authorisations provided that the MA holder commits to provide further information when available (eg samples of finished packs, ongoing stability data etc.). These are sometimes forgotten in the push to get a new product marketed and distributed. The Product Quality Review is a good time to confirm that these commitments have been fulfilled.

Qualification status of relevant equipment and utilities

Are utility systems such as HVAC, water or compressed gases still working appropriately? Have ongoing testing or monitoring results been reviewed for trends or failures? What investigations were carried out and were any corrective actions effective? Have any changes been made to these systems, and was requalification carried out?

Technical Agreements

Are there Technical Agreements with all suppliers and contractors, and are they up to date? Do they adequately reflect the activities and responsibilities of each party, and meet the requirements of the GMP guidelines?

Unlike the FDA Annual Product Review, there is no defined format for the completed report. The company is able to choose the format that is most appropriate for the product and the quality system.

Companies will need to establish where the information is currently held, and set up procedures and agreements to obtain it. While the final document must be assessed and signed off by the Qualified Person and the Marketing Authorisation holder, it would be acceptable to outsource the assembly and review of the raw data to an expert consultant.

Medicines Inspectors will be expecting to see the first Product Quality Review Reports, for a minimum review period of at least six months, during their inspections in 2006. Subsequent reports should cover the full twelve months review period.

It will require a significant resource to assemble, collate and review all of these data, but the cost savings from reduced batch failures and improved regulatory compliance should outweigh the cost of producing these reviews.