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Pharma Uptoday Monthly Magazine Volume 7 issue Oct 2014

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To recap the previous month's pharma highlights to Pharma group, Monthly magazine Volume 7 has been released with

3 News Uptoday

30 New Guidance and New MAPP Release

37 Audit Findings

483 Observations

- 483 of Alexander Infusion

Warning Letters

- John W Hollis Inc.

EMA Non-Compliance Reports

- Hebei Dongfeng Pharmaceutical Co., Ltd, China

- I.C.I. International Chemical Industry, Italy

41 Regulations of the Month

§211.184 Component, drug product container, closure, and labeling records

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Pharma Uptoday Monthly Magazine Volume 7 issue Oct 2014

  1. 1. For feedback, suggestions & queries write to us on “pharmauptoday@gmail.com” To subscribe free online pharma newsletter write a mail to “pharmauptoday@gmail.com” with subject “Add mail”. PHARMA UPTODAY VOLUME: 7 - ISSUE: OCT 2014 |
  2. 2. PHARMA UPTODAY 2 Inside this issue 3 News Uptoday 30 New Guidance and New MAPP Release 37 Audit Findings 483 Observations - 483 of Alexander Infusion Warning Letters - John W Hollis Inc. EMA Non-Compliance Reports - Hebei Dongfeng Pharmaceutical Co., Ltd, China - I.C.I. International Chemical Industry, Italy 41 Regulations of the Month §211.184 Component, drug product container, closure, and labeling records
  3. 3. PHARMA UPTODAY 3 News Uptoday Health Canada releases Inspectorate Program Annual Inspection Summary Report 2013-2014 Chapter 4 Drug Good Manufacturing Practices (GMP) Inspection Program Background As part of the Inspectorate's role of delivering a national compliance and enforcement program, drug establishment inspections against the Good Manufacturing Practices (GMP) help ensure drugs are consistently produced and controlled to meet quality standards appropriate to their intended use. In the FY 2013-2014 the Inspectorate was responsible for conducting inspections of establishments involved in the fabrication, packaging/labelling, testing, importation, distribution or wholesaling of the category of drugs listed in Table II of Section C.01A.008 of the Food and Drug Regulations. These inspections were conducted to verify the compliance with GMP requirements as outlined in the Food and Drug Regulations, which is a requirement for the issuance of an Establishment Licence. The initial inspection of an establishment is triggered by the receipt of a Drug Establishment Licence Application. The Inspectorate endeavours to perform an initial onsite inspection within three months of the date of receipt of a complete Drug Establishment Licence Application. A regular inspection is then conducted within 12 months of the initial inspection. After that, the date of subsequent inspections depends on the activities being conducted by the establishment. Fabricators, packagers/labelers and testing labs are inspected on a two-year cycle. Importers, wholesalers and distributors are inspected on a three-year cycle. If an establishment is conducting multiple activities concurrently, the higher risk activity dictates the inspection cycle. Given the global nature of the drug manufacturing business, not all drug products available in Canada are manufactured in Canada. Mutual Recognition Agreements (MRA) are established based on the mutual evaluation of equivalency of regulatory frameworks. Once in place, the import of drugs from MRA countries is facilitated through the exchange of a Certificate of Compliance instead of a full paper review or on-site inspection. For non-MRA countries, to ensure the GMP compliance of foreign sites that fabricate, package/label or test drugs to be imported into Canada, Health Canada reviews the inspection reports of trusted regulatory partners. Where such inspections are not available for a foreign site, or upon the request of an importer, Health Canada may conduct an inspection. The decision to inspect a foreign site is based on several criteria such as the compliance history of the site, the nature of the drug products manufactured, the risk level of the activities taking place (e.g. sterile manufacturing), the location, the date of the last inspection and the overall risk assigned to the site, among other factors. In FY 2013-2014, the Inspectorate conducted 1,275 drug foreign site paper reviews and 13 foreign site inspections. Also in the past year, the MRA with Slovenia was operationalised and the MRA with the United Kingdom was expanded to include veterinary drugs. Inspection Results and Statistics In FY 2013-2014, 428 domestic Drug GMP inspections were conducted and 411 inspections resulted in the issuance of a compliant rating. Additionally, 13 foreign on-site drug GMP inspections were conducted, and 12 sites received a compliant rating. One establishment may be licensed for multiple activities, thus the total number of actual establishments is not equal to the total number of licence holders depicted for each activity in Figure 4.1.
  4. 4. PHARMA UPTODAY Figure 4.1 Proportion of Drug Establishment Licence (DEL) holders by activity. (FY: April 1, 2013 - March 31, 2014) 4 Regulatory Sections Cited most Frequently A total of 2,933 observations were noted during the 428 inspections conducted in FY 2013-2014. The majority of observations were cited against requirements for the quality control department C.02.013-15, Manufacturing Control C.02.011-12, and Records C.02.020-24 as shown in Figure 4.2. Examples of these observations are listed in Table 4.1. Figure 4.2 The top ten sections of the Food and Drug Regulations most frequently cited as a percentage of the total number of observations cited during inspections conducted nationally. (FY: April 1, 2013 - March 31, 2014)
  5. 5. PHARMA UPTODAY Table 4.1 Examples of observations from frequently cited sections of the Food and Drug Regulations - Good Manufacturing Practices Inspections 5 Risk Ratings of Observations During the 428 inspections 2,933 observations were noted. The majority of these observations were assigned a Risk 3 and 2 rating (50% and 49%, respectively), with the remaining observations being Risk 1 (1%) as shown in Figure 4.3.
  6. 6. PHARMA UPTODAY Figure 4.3 Distribution of risk ratings of observations during Good Manufacturing Practices inspections conducted nationally. (FY: April 1, 2013 - March 31, 2014) Of the 32 Risk 1 observations, the highest number were recorded under C.02.013-15 Quality Control (12), followed by C.02.029 Sterile Products (8) as shown in Figure 4.4. Given the high risk associated with the potential contamination of sterile products, this is generally the regulation most frequently attributed a Risk 1 rating (See the 2006-2011 Summary Report of the Drug Good Manufacturing Practices (GMP) Inspection Program and the 2012-2013 Annual Inspection Summary Report). Figure 4.4 Sections of the Food and Drug Regulations cited as Risk 1 observations during inspections conducted nationally. (FY: April 1, 2013 - March 31, 2014) 6 Forward Planning: FY 2014-2015 Key Priorities The future vision for the GMP program is to continue to apply the risk-based approach to all GMP activities. As such, key priorities are focussed on achieving efficiencies in program review, processes, structure and stakeholder engagement. The key priorities for the GMP program will be: 1) enhancing the risk management process by developing tools to achieve operational efficiencies in managing and responding to emerging risk issues to create predictability and consistency, 2) collaborating with international partners to increase mutual reliance (i.e., MRA, Pharmaceutical Inspection Cooperation/Scheme [PIC/S], RCC [Regulatory Cooperation Council] and RCI[Regulatory Cooperation Initiative]), 3) continued development and implementation of a new business model for reviewing foreign site GMP evidence, and 4) Data analysis to develop a risk-based strategy for the Active Pharmaceutical Ingredient (API) inspection program.
  7. 7. PHARMA UPTODAY FDA reminds health care professionals and consumers not to use sterile products from Downing Labs/NuVision Pharmacy of Texas Products may still pose serious risk to patients The U.S. Food and Drug Administration is reminding health care professionals and consumers about safety concerns with all sterile-use drug products made and distributed by Downing Labs LLC, doing business as NuVision Pharmacy, in Dallas, Texas. Health care professionals should not use any NuVision/Downing Labs sterile products for their patients because the firm cannot ensure the safety or quality of these products. Administration of a non-sterile drug product may result in serious and potentially life-threatening infection or death. The FDA has issued a formal request to Downing Labs for the immediate recall of all lots of its purportedly sterile products currently on the market that are not expired. In the letter, the FDA outlined poor conditions and practices identified by FDA investigators during a July 2014 inspection of Downing Labs‘ Dallas facility. In the letter, the FDA outlined the practices and facility conditions that raise concerns about the sterility assurance of purportedly sterile drug products made at the Downing Labs facility. ―Patient safety is our top priority. We recommend health care professionals stop prescribing sterile drugs from Downing Labs because they pose serious potential risks to patients,‖ said Janet Woodcock, M.D., director of the FDA‘s Center for Drug Evaluation and Research. ―Patients deserve medications that are safe, effective, and of high quality no matter who makes them, and the FDA will continue to take action to protect patients.‖ The FDA‘s recent inspection of the Downing Labs facility revealed sterility failures in 19 lots of drug products intended to be sterile, endotoxin failures in three lots of drug products, and inadequate or no investigation of these failures. Endotoxins are substances found in certain bacteria that cause a wide variety of serious reactions such as fever, shock, and changes in blood pressure and in other circulatory functions. The FDA alerted health care professionals not to use purportedly sterile drugs from NuVision/Downing Labs due to possible contamination on July 18, 2014. Previously, on July 26, 2013, after observing poor conditions and practices during a March – April 2013 inspection, the FDA formally requested NuVision Pharmacy recall all sterile use drug products. The FDA reminds health care professionals to check their medical supplies, quarantine any purportedly sterile drug products prepared at the Downing Labs facility, and not administer them to patients. Products made at the Downing Labs facility are distributed nationwide. Most of the product labels include: NuVision Pharmacy, Dallas Texas 75244. 1-800-914-7435. Patients who have received any drug product produced at the Downing Labs facility and have concerns should contact their health care professional. The FDA is not aware of recent reports of illness associated with the use of these products. The FDA asks health care providers and consumers to report adverse reactions or quality problems experienced with the use of any products made at the Downing Labs facility to the FDA‘s MedWatch Adverse Event Reporting program by:  completing and submitting the report online at www.fda.gov/medwatch/report.htm; or  downloading and completing the form, then submitting it via fax to 1-800-FDA-0178. 7
  8. 8. PHARMA UPTODAY The FDA, an agency within the U.S. Department of Health and Human Services, protects public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation‘s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products. UK drug regulator inspects Wockhardt Chikalthana unit Drug maker Wockhardt‘s manufacturing facility in Chikalthana, near Aurangabad in Maharashtra, was inspected earlier this week by the British drug regulator, Medicines and Healthcare Products Regulatory Agency (MHRA), it is learnt. The facility, banned from the American market, is currently under tight scrutiny of the UK regulator. An e-mail query to Wockhardt didn‘t elicit a response. When asked, an MHRA spokesperson said, ―We are continuing to assess the corrective actions implemented at Wockhardt‘s Indian manufacturing plants and the progress the company is making towards compliance with EU (European Union) good manufacturing practice.‖ The regulator said the assessment includes an ongoing programme of manufacturing site inspections and written updates from the company. Last October, MHRA, one of the prominent international health regulators, withdrew its quality certification to the Chikalthana unit. This was after it identified manufacturing deficiencies in the plant during a site inspection. The regulator had also initiated a recall of several prescription medicines made at the factory. However, it allowed the company to continue exporting some critical drugs to the UK, to avoid a shortage. The Chikalthana facility is also under an ‗import alert‘ of US Food and Drug Administration (FDA). In fact, reports suggest, the two foreign regulators had conducted a joint inspection of the plant in July last year. After that, the FDA listed observations highlighting deficiencies in quality control, the same month. The company failed to address these in time, triggering a ban on supplies from the unit to the American market. Indian Patients Suffer from India’s Weak Pharmaceutical Patents India‘s recently elected Prime Minister, Narendra Modi, will visit the United States later this month. One of the sticking points in the U.S.-India relationship is weakness in India‘s laws governing intellectual property (IP). The Global Intellectual Property Center of the U.S. Chamber of Commerce ranks 25 countries in its Global IP Index, and India comes in last place. Indian growth will continue to lag as long as this persists, as researchers have demonstrated the positive relationship between IP protection and a country‘s prosperity. One of India‘s weak spots is patent protection for new prescription drugs. New research also shows, counterintuitively, that this limits patients‘ access to new medicines. Professors Ernst R. Berndt and Ian M. Cockburn analyzed the 184 new medicines approved by the U.S. Food and Drug Administration between 2000 and 2009. Shockingly, it took more than five years for half of those drugs to become available in India. Ten years after being launched in the United States or elsewhere, almost one quarter of the new medicines were still not available in India. The authors also compared when the drugs were available in other developed countries. For example, in 2010, 160 of the new medicines were available in Germany, but only 111 were available in India. 8
  9. 9. PHARMA UPTODAY Berndt and Cockburn conclude that India‘s patent law is to blame for this long lag in access versus the United States and other countries. The authors found that half of the new medicines faced copycats within one year of launching in India, and 85 percent faced copycats within three years. In Germany, by contrast, none of the drugs faced copycats within five years. These results indicate that effective patent protection is not available for most prescription drugs in India. So, it is unsurprising that innovative drug-makers are reluctant to sell their medicines there. Investors are also unlikely to put their capital at risk in Indian drug companies that seek to discover new medicines. It appears to be a lose-lose situation: An innovative pharmaceutical industry is unlikely to grow out of India, and Indian patients will continue to be deprived of new medicines, until India‘s patent law is fixed. The new government recognizes the need for laws that protect intellectual property. However, it has not yet announced decisive steps to improve this situation. Why the delay, in the face of mounting evidence of harm? India has a world-leading generic pharmaceutical industry, which rose to global prominence largely because India had no pharmaceutical patents at all until 2005. India could not take full advantage of international free trade without signing onto international treaties meant to level the playing field. So, India started granting pharmaceutical patents. However, they are limited in important ways, and Indian jurisprudence has confirmed innovative firms‘ lack of confidence in the patent regime. India‘s generic drug industry is an important national asset, which benefits patients worldwide. It is unlikely that U.S. patients would be able to buy a month‘s worth of generic medicines for four dollars without Indian generic drug-makers competing in the market. However, a strong branded pharmaceutical industry and a strong generic industry are not mutually exclusive. The United States and other developed countries have successful, home-grown generic competitors as well as brand-name drug-makers. Indian patients and Indian medical innovation will benefit when India improves its patent law to the highest global standard. Cipla buys Indian plants from contractor Indian drugmaker Cipla has bought two manufacturing facilities from its contractor Okasa Pharma. The INR100m ($16m) deal, which was detailed in a filing on the Bombay Stock Exchange (BSE) on Monday, adds a multi-dosage form plant in Goa and an aerosol formulations site in Satara to Cipla‘s network and it being conducted by its subsidiary Medispral Laboratories. The drugmaker said that: ―A significant portion of the capacities of the two undertakings are dedicated for the manufacture of Cipla's products. Acquisition of the aforesaid undertakings is expected to yield operational synergies.‖ News of the deal comes just months after Cipla unveiled plans to invest in its UK manufacturing subsidiary and acquired fellow India-based cell banking, cell culture, purification and formulation firm Mabpharm. Industry groups take issue with FDA draft guidance on outsourcing facilities Industry groups BIO (Biotechnology Industry Association) and GPhA (Generic Pharmaceutical Association) are calling for outsourcing facilities to be held to the same standards as other, larger manufacturers. The FDA‘s draft guidance , released in July, recognizes the differences between outsourcing facilities and commercial drug manufacturers and looks to tailor the cGMP (current good manufacturing practice) requirements to the unique needs of the compounding industry. 9
  10. 10. PHARMA UPTODAY However, both BIO and GPhA call on the FDA to make a distinction within cGMP requirements between (a) sterile drug products that are compounded by the aseptic combination of licensed, commercially manufactured sterile drug products under aseptic conditions (sterile-to-sterile [S-S]) and (b) sterile drug products that are compounded from non-sterile bulk active pharmaceutical ingredients(API) ―since the risks associated with the compounded drug product differs between these two types of products, necessitating different controls.‖ Same Criteria Both industry groups also call for a somewhat level playing field for compounders and other drug manufacturers. GPhA says compounders and outsourcing facilities should abide by the same inspection criteria as other drug manufacturers. ―Drug manufacturers with U.S-based facilities are required to be inspected by FDA at least every 24 months,‖ GPhA says. ―Compounders producing sterile products should be held to similar standards.‖ Similarly, BIO disagrees with FDA‘s proposed alternative approaches for reducing the need for laboratory testing of incoming components and to minimize the need for facilities to have an in-house laboratory. ―We believe that the alternative approach to testing should not be permitted exclusively for outsourcing facilities,‖ BIO says. ―These sites should be accountable for maintaining the same level of control over their contract sites as would any other pharmaceutical manufacturer.‖ And while outsourcing facilities may contract release testing to an outside laboratory, BIO believes ―that they should be required to comply with the same requirements and expectations as would need to be met by a pharmaceutical manufacturer. It is important that FDA apply the same well established and standard industry requirements to ensure adequate and consistent protection of public health.‖ BIO also makes note that outsourcing facilities ―are not exempt from the obligations that manufacturers of biological products must satisfy,‖ and the group ―recommends that the Agency clearly state that this Guidance only applies to small molecule products that are approved under the Federal Food, Drug and Cosmetic Act (FFDCA) and not to biological products approved under the Public Health Service Act (PHSA).‖ Pharmacists Unlike BIO and GPhA, ASHP (Association of Health-System Pharmacists), however, is largely supportive of FDA‘s moves to relieve the compounding industry from burdensome new regulations. It says it ―supports the FDA‟s alternative approach to minimize the need for facilities to have an in-house laboratory. Having testing performed by a third party registered with the FDA would improve confidence in the accuracy of the testing procedures and results. Having a uniform set of standards for laboratories to meet under this approach would also have the added benefit of consistency across end-product testing standards.‖ ASHP also says it ―supports the FDA‟s various conditions place on outsourcing facilities to verify the identity and integrity of incoming components used in compounding.‖ 10 Commentary Regarding new USP Chapters <787> and <1787> for Particulate Matter Guidance During the current (2010-2015) USP Expert Committee cycle, the Dosage Forms Expert Committee has developed both new and revised general chapters that provide guidance on particulate matter content of injectable drug products. For visible particles, methods are based upon human detection sensitivity as described in Visible Particulates in Injections <790>, which applies to all sterile injectable dosage forms. For subvisible particle content, which is based upon instrumental determination, new particulate matter guidance has been established specifically for sterile injectable biotherapeutic products.
  11. 11. PHARMA UPTODAY The new general chapter Subvisible Particulate Matter in Therapeutic Protein Injections <787> became official August 1, 2014, and provides an improved version of the approach in the chapter Particulate Matter in Injections <788> for the more-sensitive protein formulations. Chapter <787> was initiated to modify historical <788> testing by light obscuration, in order to address the sensitivities of protein products. Chapter <787> also provides a testing framework for a scientific and regulatory concern regarding the immunological effects of the sub-10-μm particle load. In addition, smaller-volume sampling is allowed, down to 0.2-mL aliquots, and sampling of individual containers as well as gentler de-gassing steps is included. Although particle-size thresholds remain the same at >= 10 μm and >=25 μm, with the same limits as those found in chapter <788>, there is a recommendation to monitor the population below the 10 μm threshold. Total particle content is limited to 6,000 particles >=10 μm and 600 particles >= 25 μm for all dosage forms. The new informational chapter Measurement of Subvisible Particulate Matter in Therapeutic Protein Injections <1787> was developed to support chapter <787> and provides sizing, counting, and characterization guidance for all protein therapeutic products; <1787> provides significant expansion of recommended techniques. The new chapter will appear in USP 38 in November and become official May 1, 2015. As an informational chapter, it provides no count limits but instead is focused on the determination of the inherent protein population and its character. The intent of chapter <1787> is to aid the scientific development process for all therapeutic protein products. The chapter provides guidance on subvisible particles in the 2-μm to 100-μm range. The rationale for using this range is based upon 100 μm as a conservative, lower-limit threshold for visible particles and 2 μm as the lower size domain for which the recommended techniques are considered robust and proven. The informational chapter is presented in three sections: Size and Distribution, Size and Morphology, and Characterization, with descriptions of techniques in each section. Advantages and disadvantages of each technique are presented. The chapter also provides definition and discussion of the three particle categories: a) extrinsic (truly foreign), b) intrinsic (unwanted yet arising from the process or product), and c) inherent (product attribute). A discussion of silicone oil content is included; even though silicone oil is a necessary additive for most products, it may produce artifact counts or unwanted particles, or it may affect the stability of the therapeutic agent if uncontrolled or used in excessive quantity. It is recommended that data on the population below 10-μm is collected in two data bins: >= 2-5 μm and >= 5-10 μm. Chapter <1787> concerns all particle species present in the final product; however, it is primarily oriented toward the inherent therapeutic agent condition and acceptability. Certainly, the acceptability of the therapeutic protein product is dependent upon the innovator data and regulatory review. Sun Pharma shares dip 4% on ‘surprise’ USFDA inspection news Shares of Sun Pharmaceutical Industries ended with a loss of more than 4 per cent on Thursday on reports that its Halol manufacturing plant in Gujarat was subjected to surprise inspection by the American drug regulator United States Food and Drug Administration. The stock, which touched a high of ₹850.70 on the NSE, dropped to a low of ₹808 before recovering to ₹821 at close, a loss of ₹36.80 or 4.29 per cent.. No information was posted on their websites by the stock exchanges till the end of trading about any response from the company regarding the reported inspection. But there was a market buzz about it, leading to the stock coming under pressure. Sarabjit Kour Nangra, VP — Research (Pharma), Angel Broking, said that it was learnt that Sun Pharma‘s manufacturing facility at Halol (Gujarat) ―is undergoing a surprise inspection by the USFDA.‖ The action might be a fallout of a ―number of recent recalls from the plant,‖ she said quoting sources ―familiar with the development.‖ 11
  12. 12. PHARMA UPTODAY According to Credit Suisse, which recently rated the stock ‗outperform‘ with a revised price target of ₹950 (up from earlier ₹900), key risk remains pending FDA inspection at Halol facility (nearly 25 per cent of profits). Nangra said in May Sun Pharma‘s unit in Karkhadi in Gujarat was warned by the USFDA ―after investigators identified violations of current good manufacturing practices and regulations for finished pharmaceuticals.‖ She mentioned about Sun Pharma recalling three important medicines from the US market, all of which were produced at Halol. 12 May hit in profits She said that the contribution of the Halol plant to overall sales might decline (expected to be around 10 per cent of sales in FY16). While profitability could be hit, it was ―too early to call given that the company has voluntarily done some withdrawal, and given the importance of the facility.‖ Research in regulatory science is need of the hour; Experts Emphasizing the fact that regulatory science is an evolving discipline and that there is a need to promote regulatory science research in the country, experts deliberated on harmonisation of regulations existing globally to make quality medicines available on the occasion of 4th Technical Seminar was held in Mumbai from September 9 to 10, 2014 by Indian Pharmaceutical Association (IPA) in association with the European Directorate for the Quality of Medicines and Healthcare (EDQM). The theme of the conference was on ‗Quality of Pharmaceutical Ingredients: Applying Learnings to Practice'. Advocating the need for training the pharma industry workforce in line with the global regulatory needs, experts said that this becomes more pertinent as there are diverse regulatory environment and constraints, different history and working principles, diverse source of material in pharma manufacturing and different decision making processes in different countries. Speaking on the sidelines of the event, Dr G N Singh, Drug Controller General of India (DCGI) said that there is a need for upgrading the standards of Good Manufacturing Practices (GMP) along with harmonisation of laws. India is poised to gain the advantage in the process of harmonisation as it supplies generics to 205 countries globally." Echoing similar views on India's delivery of quality medicines globally, Dr B Suresh, president, PCI, said, "Among other issues related to data integrity, Current Good Manufacturing Practices (cGMP), manufacturing deficiencies, electronic data controls, workforce training in the pharma industry need to be met on an urgent basis." Talking about workforce training in the pharma industry Dr Susanne Keitel, director, EDQM said that a consortium of agencies in association with EDQM is planning to run a series of training programmes for all the stakeholders of the Indian pharma industry by the end of this year. Discussions on the same are currently going on. Experts pinpointed that there is a regulatory vacuum and no clarity on regulations when it comes to talking about India besides the fact that regulatory system is mired by multiple controls. The Indian
  13. 13. PHARMA UPTODAY pharma is market driven and enforcement by regulatory agencies is lax. Workforce training is therefore the need of the hour in regulatory agencies and pharma industry. S D Joag, secretary general, Indian Pharmaceutical Association (IPA) said that regulatory science in India should be incorporated in academics and should be industry driven. Research in regulatory science is the need of the hour. Adding to it Dr Suresh explained that pharma workforce should be upgraded in areas like biostatistics, decision theory and information technology, clinical trial design, clinical research and drug and device design and discovery. Courses like MSc in medical technology regulations and regulatory affairs should be introduced in the academics. Other speakers on the event - Dr Aniruddh Vaidya from Analytical Solutions spoke on 'Pharmaceutical products –Extractables and Leachables concept', Dr Vinay Nayak, president, Alembic Pharmaceuticals on 'Pharmacopoeia Harmonization –Indian Perspectives and Challenges' and Dr Prashant Dixit, general manager, analytical research, Watson Pharma on 'Pharmaceutical Reference Standards'. 13 Current FDA's Warning Letters on IT Topics : Finished Medicinal Products and APIs In a first stage of escalation - when serious GMP deviations are identified during inspections, or in case of insufficient corrective measures - the FDA issues a Warning Letter to the companies concerned. Within 15 working days, the companies in question have to undertake concrete action plans to redress those deviations. If these action plans are evaluated as insufficient by the Agency, further escalation levels may follow. Some Warning Letters from 2014 also list GMP deficiencies with regard to IT topics. Not a single Warning Letter has been exclusively issued just because of IT issues, though. But taken together, all the GMP deviations in a company were so serious that the Agency issued a Warning Letter which also included deviations related to IT. All in all, 7 Warning Letters from 2014 contain topics with regard to IT. 4 Warning Letters have been issued for manufacturers of medical devices, 2 Warning Letters for manufacturers of medicinal products and 1 Warning Letter for an API manufacturer. Following you will find letters with regard to finished medicinal products and APIs. IT-related Warning Letters on finished medicinal products and APIs IT-related Warning Letters for manufacturers of finished medicinal products always refer to 21 CFR 211.68 (b): "Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records "21 CFR 211.68 (b)" . With regard to that area, the Warning Letter issued for the company USV Limited criticises many items and has generally recorded the absence of appropriate provisions for the application of computerised systems. In detail, the following critical points are mentioned:  Current computer users in der laboratory were able to delete data from analyses  The audit trail function for a GC and a XRD system was disabled at the time of the inspection. Therefore the firm lacks records for the acquisition, or modification, of laboratory data  QC lab personnel shared login IDs for HPLC units. The lab staff shared one login ID for the XRD unit. Analysts also shared the username and password for the Windows operating system for the GC workstation and no computer lock mechanism had been configured to prevent unauthorized access to the operation system  There was no procedure for the backup and protection of data on the GC standalone workstations
  14. 14. PHARMA UPTODAY  In the response the firm lacks assurance that the periodic backed up data include all of 14 the original data generated  Also the questions regarding Audit Trails and access controls have been either unanswered or insufficiently answered. Also the Warning Letter for the company Sun Pharmaceutical Industries lists several critical comments:  Numerous deleted raw data files on computers used for the GC instruments in the QC lab. The software on the computers used to control the GC instruments allowed the analysts to delete files from the hard drive with no audit trail or adequate form of traceability in the operating system to document deletion activity  The software as configured assigned sequential, numerical names to raw data files within the same folder. When a raw data file was deleted or moved out of the designated folder, the next file recorded into the folder would be saved with an identical name as the deleted file. As a result, data can be manipulated so that saved files appear to be in sequence even if they were not generated sequentially  Due to the basic lack of audit trail and data security, an analyst could delete analytical files without traceability - an unacceptable practice from the FDAs point of view The Warning Letter for the API manufacturer Trifarma doesn't refer to the respective sections from the CFR. Yet, here again it focused on possible unauthorised manipulation of raw data in the lab. Corresponding provisions were inexistent. Concretely, the following aspects have been addressed:  The laboratory systems did not have access controls to prevent deletion or alteration of raw data  All laboratory employees were granted full privileges to the computer systems  HPLC and GC computer software lacked active audit trail functions to record changes to data, including information on original results, the identity of the person making the change, and the date of the change  The response did not describe the audit trails for the processing of the data on your system.  The response also states the firm has begun to retain electronic raw data on the local hard drive, but without proper safeguards to ensure they cannot be deleted prematurely From the authority's view, the current focus of IT-topics generally concerns the question of data and system security, particularly the traceability of changes by means of Audit Trails. Industry groups take issue with FDA draft guidance on outsourcing facilities Industry groups BIO (Biotechnology Industry Association) and GPhA (Generic Pharmaceutical Association) are calling for outsourcing facilities to be held to the same standards as other, larger manufacturers. The FDA‘s draft guidance , released in July, recognizes the differences between outsourcing facilities and commercial drug manufacturers and looks to tailor the cGMP (current good manufacturing practice) requirements to the unique needs of the compounding industry.
  15. 15. PHARMA UPTODAY However, both BIO and GPhA call on the FDA to make a distinction within cGMP requirements between (a) sterile drug products that are compounded by the aseptic combination of licensed, commercially manufactured sterile drug products under aseptic conditions (sterile-to-sterile [S-S]) and (b) sterile drug products that are compounded from non-sterile bulk active pharmaceutical ingredients(API) ―since the risks associated with the compounded drug product differs between these two types of products, necessitating different controls.‖ Same Criteria Both industry groups also call for a somewhat level playing field for compounders and other drug manufacturers. GPhA says compounders and outsourcing facilities should abide by the same inspection criteria as other drug manufacturers. ―Drug manufacturers with U.S-based facilities are required to be inspected by FDA at least every 24 months,‖ GPhA says. ―Compounders producing sterile products should be held to similar standards.‖ Similarly, BIO disagrees with FDA‘s proposed alternative approaches for reducing the need for laboratory testing of incoming components and to minimize the need for facilities to have an in-house laboratory. ―We believe that the alternative approach to testing should not be permitted exclusively for outsourcing facilities,‖ BIO says. ―These sites should be accountable for maintaining the same level of control over their contract sites as would any other pharmaceutical manufacturer.‖ And while outsourcing facilities may contract release testing to an outside laboratory, BIO believes ―that they should be required to comply with the same requirements and expectations as would need to be met by a pharmaceutical manufacturer. It is important that FDA apply the same well established and standard industry requirements to ensure adequate and consistent protection of public health.‖ BIO also makes note that outsourcing facilities ―are not exempt from the obligations that manufacturers of biological products must satisfy,‖ and the group ―recommends that the Agency clearly state that this Guidance only applies to small molecule products that are approved under the Federal Food, Drug and Cosmetic Act (FFDCA) and not to biological products approved under the Public Health Service Act (PHSA).‖ Pharmacists Unlike BIO and GPhA, ASHP (Association of Health-System Pharmacists), however, is largely supportive of FDA‘s moves to relieve the compounding industry from burdensome new regulations. It says it ―supports the FDA‟s alternative approach to minimize the need for facilities to have an in-house laboratory. Having testing performed by a third party registered with the FDA would improve confidence in the accuracy of the testing procedures and results. Having a uniform set of standards for laboratories to meet under this approach would also have the added benefit of consistency across end-product testing standards.‖ ASHP also says it ―supports the FDA‟s various conditions place on outsourcing facilities to verify the identity and integrity of incoming components used in compounding.‖ Government to hear out US pharma companies' patent fears After months of skirmishes, the government is finally going to sit down with American pharma giants this week to hear out their concerns, a move that comes weeks before Prime Minister Narendra Modi leaves for the US. Sources told that commerce secretary Rajeev Kher will hold discussions with the drug companies that have been critical of India's intellectual property rights regime, especially over the use of compulsory licensing provisions that resulted in patent rights waiver for a cancer medicine. The other area of concern is the use of provisions to deny patents to medicines on the grounds that they lack innovation. 15
  16. 16. PHARMA UPTODAY Big Pharma had got the US government to put pressure on Indian authorities but New Delhi has refused to budge so far. "It will be more of hearing them out and giving our point of view. We aren't changing our position," said an officer. India has repeatedly argued that it's IPR regime is in line with its commitment to WTO's Trips Agreement. The meeting itself is the fallout of discussions by a committee of secretaries, where it was felt that the government should engage with the companies. In recent weeks there have been signals that India and US are willing to engage. Later this week, deputy US trade representative Wendy Cutler will be in Delhi to prepare ground for ministerial-level deliberations on trade and investment following Modi-Obama meeting. On Friday, a senior US official met commerce and industry minister Nirmala Sitharaman, where the US comforted India on WTO talks and suggested that it is willing to work for a solution, said officials familiar with the discussions. Sitharaman, on her part, is said to have stayed firm on India's stand that India will sign the trade facilitation agreement only if there is a permanent solution to its food security concerns. 16 Form 483 action looms over Sun's Halol plant The recent US Food and Drug Administration (FDA) surprise visit at Sun Pharmaceutical Industries's Halol facility may lead to an issuance of Form 483, potentially a precursor to an import alert. The US FDA last week conducted a surprise inspection at company's Halol facility in Gujarat, which contributes nearly 15-20% to Sun Pharma's US sales. Recalls of various drugs made at the unit was seen as a trigger for the inspection. According to an industry expert, US FDA now has its office in India and a surprise inspection in any facility of any pharma company is therefore a possibility now. The whole motive is to check whether these companies are maintaining the manufacturing and quality standards as laid out by the FDA, the expert said. FDA issues Form 483 to a company at the conclusion of inspection in which the investigators observe conditions that they think violate the Food Drug and Cosmetic Act and related Acts. Form 483 notifies the company of objectionable conditions. The company is encouraged to respond with a corrective action plan followed by its implementation. Else, an import alert could be issued against the company. "What we understand is that FDA has made certain observations which include some data and record related observation as well. Some deviations may have occurred in relation to documentations. If FDA thinks these are serious in nature, it may lead to a Form 483," said another industry expert. Hitesh Mahida, analyst with Antique Stock Broking, said, "The facility was last inspected in 2012. So in that sense the FDA inspection is not something unusual, since FDA can carry out such inspections once in every two years. But if they are not satisfied with the manufacturing standards and have witnessed deviations, it might then lead to a Form 483. Halol is one of the major facilities for Sun Pharma and a warning letter will cause a major setback for the company." Sun Pharma's Karkhadi facility, also in Gujarat, is under import ban from FDA. Though the impact is insignificant in terms of sales but the observations were serious in nature. FDA has identified violations of current good manufacturing practice (CGMP) regulations for its finished pharmaceuticals and deviations from CGMP for the manufacture of APIs in the facility. "If the deviations or the violations observed in case of Halol are similar in nature to what it was with Karkhadi, then it can lead to a serious impact going forward," said another sector analyst. Sun Pharma
  17. 17. PHARMA UPTODAY in April announced its intent to acquire Ranbaxy Labs, which is facing import ban from FDA on four of its plants in India. "With Sun acquiring Ranbaxy, FDA is also more likely to keep a close watch on the former," said an expert. In a latest update on BSE, Sun Pharma has said that it will seek shareholders' approval to raise Rs 12,000 crore via qualified institutional placement. It will also seek a similar approval for borrowing, in tranches, for up to Rs 50,000 crore. Mahida said, "The company wants shareholders' approval so that it can raise and utilise the money for any future expansion and M&As." 17 Pfizer, Ranbaxy win dismissal of lawsuit over generic Lipitor Pfizer Inc and India's Ranbaxy Laboratories Ltd on Friday won dismissal of an antitrust lawsuit accusing them of conspiring to delay sales of generic versions of the cholesterol drug Lipitor, the best-selling drug in history. U.S. District Judge Peter Sheridan in Trenton, New Jersey ruled that the plaintiffs, retailers and distribution companies that bought Lipitor directly from Pfizer, failed to plead their case with enough detail. The lawsuit was filed in 2012 by retailers and distributors that bought Lipitor directly from Pfizer. The lawsuit stems from a 2008 settlement of a patent lawsuit filed by Pfizer against Ranbaxy over Ranbaxy's plan to make generic Lipitor. Under the deal, Pfizer agreed to drop a claim for damages against Ranbaxy, and Ranbaxy agreed to stay out of the Lipitor market until November 2011. Retailers and distribution companies claim that the settlement amounted to Pfizer paying Ranbaxy to stay out of the Lipitor market, violating antitrust laws. But Sheridan ruled Friday that their case failed because they did not offer any allegation of the settlement's dollar value. Sheridan dismissed another version of the lawsuit last September. Lawyers for the plaintiffs and a Pfizer spokesman could not immediately be reached for comment. More new rules for trial sponsors and CROs in India Drugmakers sponsoring trials in India will need to weigh the potential risks and benefits for the people who take part under new guidelines issued by the CDSCO. The requirement – set out in a document published this month – is designed to bring the trial application process into line with an order issued in October by the Indian Supreme Court in response to a petition filed by study ethics organisation, Swasthya Adhikar Manch . Swasthya Adhikar Manch, which campaigns for the rights of clinical trial participants in India, has been lobbying Government officials to tighten up the rules that govern trials, which was acknowledged as a driver for the guidance by CDSCO. Also under the guidance, trial sponsors are required to say if the drug they are assessing is an innovation and if there is an existing therapeutic option. They must also state if the medicine is for an unmet medical need in India. The new guidance is the latest in a long list of rule revisions prompted by the Swasthya Adhikar Manch petition – which resulted in 162 studies being halted - and other ongoing Government investigations of the Indian trial sector. In July , for example, CDSCO issued new guidelines on trial design, investigator working practices and on compensation for the families of trial participants who die or are seriously injured during drug research.
  18. 18. PHARMA UPTODAY Trial approvals up on 2013 To date, efforts to impose stricter regulations on clinical research conducted in Indian do not appear to have made the country less attractive to sponsors. According to data released by CDSCO in July, 76 clinical studies had been approved by the end of May which is nearly three times as many as were given the green light during the equivalent period in 2013. Whether the number of clinical trials approved this year will top the record 262 studies that were cleared in 2012 remains to be seen. 18 Chemistry, Manufacturing, and Controls (CMC) Perspective of the IND "Chemistry, Manufacturing, and Controls (CMC) Perspective of the Investigational New Drug Application (IND)" Web-based training (WBT) course. This course focuses primarily on the CMC information for IND submissions and is not intended to include all the requirements applicable to INDs. The WBT can be accessed from the link : http://www.accessdata.fda.gov/cder/cmc/index.htm GlaxoSmithKline fined $490m by China for bribery China has fined UK pharmaceuticals firm GlaxoSmithKline $490m (£297m) after a court found it guilty of bribery. The record penalty follows allegations the drug giant paid out bribes to doctors and hospitals in order to have their products promoted. The court gave GSK's former head of Chinese operations, Mark Reilly, a suspended three-year prison sentence and he is set to be deported. Other GSK executives have also been given suspended jail sentences. The guilty verdict was delivered after a one-day trial at a court in Changsha, according to the Xinhua news agency. Chinese authorities first announced they were investigating GSK in July last year, in what has become the biggest corruption scandal to hit a foreign firm in years. The company was accused of having made an estimated $150m in illegal profits GSK said it had "published a statement of apology to the Chinese government and its people". "Reaching a conclusion in the investigation of our Chinese business is important, but this has been a deeply disappointing matter for GSK," said chief executive Sir Andrew Witty in a statement. "We have and will continue to learn from this. GSK has been in China for close to a hundred years and we remain fully committed to the country and its people," he said. "We will also continue to invest directly in the country to support the government's health care reform agenda and long-term plans for economic growth." Mick Cooper, analyst at Edison Investment Research in London, said: "GlaxoSmithKline will hope that this will draw a line under events in China, but it will take time for its Chinese commercial operations to recover." Health ministry to revise Schedule M-III for medical devices to make it harmonious with international standards The Union health ministry is contemplating to revise the Schedule M-III for medical devices under the Drugs and Cosmetics Rules, 1945 replacing the present limited Schedule M-III to address the problems of medical device industry and to make the requirements for medical devices harmonious to the international standards.
  19. 19. PHARMA UPTODAY The medical devices industry in the country has been airing the difficulties faced by the industry in respect of implementation of the provisions of the Drugs and Cosmetics Act, 1940 and Rules made thereunder regarding the implementation of Good Manufacturing Practices for medical devices. The industry has been demanding that the requirement of GMP compliance for medical devices should be as per IS: 15579: (ISO 13485) standards. The issue of compliance of Schedule M by the manufacturers of medical devices has been raised many times in the past. The Schedule M relating to the Good Manufacturing Practices for pharmaceutical products provides in the Note appended to the Schedule that in the case of certain categories of drugs including medical devices, the licensing authority have the discretion to modify the requirements of the Schedule, if he is the opinion that having regard to the nature of the products and extent of manufacturing operations and reasons to be recorded in writing, it is necessary to relax or alter them in the circumstances of a particular case and direct the manufacturer to carry out necessary modifications in them and the modifications having been made, approve the manufacture of such categories of drugs. As per these provisions, it is not mandatory that all the provisions of Schedule M are required to be complied by the manufacturers of medical devices. These could be modified and approved on case to case basis. The definition of the term ‗drug‘ under Section 3 of the Drugs and Cosmetics Act, 1940, under clause (iv) includes such devices intended for internal or external use in the diagnosis, treatment, mitigation or prevention of disease or disorder in human beings or animals, as may be specified from time to time by the Central Government. So far the government has notified 14 categories of medical devices. They are disposable hypodermic syringes; disposable hypodermic needles; disposable perfusion sets; in vitro diagnostic devices for HIV, HBsAg and HCV; cardiac stents; drug eluting stents; catheters; intra ocular lenses; I.V. cannulae; bone cements; heart valves; scalp vein set; orthopaedic implants; and internal prosthetic replacements. 19 NPPA caps prices of 43 drug formulation packs National Pharmaceutical Pricing Authority (NPPA) has capped the prices of 43 formulation packs including drugs such as antibiotic Ciprofloxacin, BCG vacine and anti-diabetic Metformin. "The prices have been fixed / revised in respect of 43 formulation packs, both ceiling and retail price packs, under DPCO, 2013," NPPA said. The drug price regulator said the manufacturers of above mentioned formulations having maximum retail price higher than the ceiling price specified shall revise the MRP to an amount not exceeding the ceiling price plus local taxes, wherever applicable in accordance with paragraph 13 (1) and 24 of the DPCO,2013. Major drug companies including Cipla, Ranbaxy, Lupin and Cadila are likely to be impacted as a result of the price control. Commenting on the development, Angel Broking VP Research - Pharma Sarabjit Kour Nangra said: "This would have near term impact on the companies." In July this year NPPA had reduced the prices of some of the key medicines and had fixed the price of 108 non-scheduled formulation packs of 50 anti-diabetes and cardiac medicines. The drugs that were to become cheaper included key medicines such as atorvastatin, gliclazide, glimepiride, hepa rin and metolazone, among others.
  20. 20. PHARMA UPTODAY 20 India's Drug War Is Good News The announcement earlier this week that U.S. pharmaceutical giant Gilead would allow seven Indian companies to make a cheap, generic version of Sovaldi -- its cure for the Hepatitis C virus and one of the world‘s best-selling drugs -- was rightfully hailed as a victory for patients in the developing world. Instead of paying $84,000 for a 12-week course of treatment as in the U.S., sufferers in India and 90 other nations will soon be able to obtain a 24-week course for less than $2,000. So why are some of the loudest protests about the deal coming from the Indian pharmaceutical industry? The main industry lobby group, which represents the 19 biggest Indian pharmaceutical firms, has come out in opposition, despite the fact that three of its members signed the deal with Gilead. The Indian Pharmaceutical Alliance insists that the science behind Sovaldi is not new and hence not subject to patent -- the same argument that allowed Indian drugmakers to churn out some $24 billion worth of other generics last year. The Alliance wants dozens of India‘s 300 established pharmaceutical companies to be allowed to produce a version of Sovaldi, not just seven of them. Ironically, Gilead‘s decision to choose Indian companies rather than those from other emerging economies, or even the U.S., was itself an acknowledgement of the competitiveness and skill of the local drug industry. It is the third largest in the world by volume and fourteenth by value (since generics are sold cheaply). Half of its revenues in 2013 were generated by exports to markets outside India. The country boasts the largest number of manufacturing facilities approved by the Food and Drug Administration outside the U.S. Originally, Indian law only recognized process, not product patents. That paved the way for an explosion of copycat manufacturing between the 1970s and 1990s. World Trade Organization rules later forced a change. But even now Indian law has a loophole disallowing patents if the science behind the discovery is not new, or if a new drug represents merely a minor modification of an older drug. The biggest Indian pharmaceutical companies would normally have united behind this position. In recent years, however, the domestic market has grown brutally competitive. The top 10 firms now command only 37 percent of the market, with no single player in double digits. The government imposes severe price controls on over 300 drugs, dampening profits. And many foreign markets remain closed to Indian-made knockoffs because of stronger patent protections. The seven companies that signed up with Gilead, which include such familiar names as Cipla and Ranbaxy Laboratories, have clearly decided that they need to adopt a different strategy to maintain profitability. Not that long ago, Cipla dramatically challenged multinational drug companies, supplying a copycat cocktail of anti-HIV drugs to sub-Saharan African countries for $350 when their international market price was $15,000. Now, the prospect of bigger margins is simply too attractive to pass up. A split in the Indian pharmaceutical industry isn‘t necessarily a bad thing for India or for the rest of the world. Critics have a fair point when they argue that $2,000 is still too expensive for patients in emerging economies, many of whom don‘t have access to insurance; the agreement also leaves out several key middle-income countries like China. But top Indian companies have to find ways to remain profitable. Some have tried to venture into original research, but the costs are high and the results unpredictable. Partnering with drug majors in the West -- whether to produce cheaper versions of drugs or to conduct outsourced research and trials -- is one obvious solution. For the global pharmaceutical industry, the fact that some Indian companies are willing to look beyond rip-off generics opens up a host of possibilities. Drug discovery is expensive, and the prospects for future cures depend on keeping the profit incentive intact. At the same time, the pressure to sell at a discount in poorer countries is not going to go away. If the Western majors can outsource this task to cost-competitive Indian companies, while cutting back the threat of indiscriminate copycat versions, they might just be able to strike a balance between profit and social responsibility. Most everyone should win -- or at least, more people than do under the current system.
  21. 21. PHARMA UPTODAY 21 India’s Micro Labs Gets FDA Import Alert For Goa Unit Import Alert # 66-40 Published Date: 09/19/2014 Type: DWPE Import Alert Name: "Detention Without Physical Examination of Drugs From Firms Which Have Not Met Drug GMPs" Reason for Alert: *** Foreign inspections of pharmaceutical manufacturers are being performed. Detention without physical examination may be appropriate when an FDA inspection has revealed that a firm is not operating in conformity with current good manufacturing practices (GMP's). Detention without physical examination may also be appropriate when FDA receives information concerning inspections conducted by foreign or other government authorities under a Memorandum of Understanding or other agreement that FDA concludes reveals conditions or practices warranting detention of either particular products or all products manufactured by a firm. DWPE of such firms remains in effect until such time as FDA is satisfied that the appearance of a violation has been removed, either by reinspection or submission of appropriate documentation to the responsible FDA Center. *** Guidance: *** Districts may detain, without physical sampling and analysis, the indicated drug products from the foreign processors noted in the Red List of this import alert. Micro Labs Limited Date Published : 09/19/2014 Plot No S-155 To S-159 , Phase III, Verna Industrial Estate , Verna, Goa INDIA 55 - - - -- Pharm Necess & Ctnr For Drug/Bio Date Published: 09/19/2014 Notes:All drugs and drug products (GMP) Good Manufacturing Practices 60 - - - -- Human and Animal Drugs Date Published: 09/19/2014 Notes:All drugs and drug products (GMP) Good Manufacturing Practices 61 - - - -- Human and Animal Drugs Date Published: 09/19/2014 Notes:All drugs and drug products (GMP) Good Manufacturing Practices 62 - - - -- Human and Animal Drugs Date Published: 09/19/2014 Notes:All drugs and drug products (GMP) Good Manufacturing Practices 63 - - - -- Human and Animal Drugs Date Published: 09/19/2014 Notes:All drugs and drug products (GMP) Good Manufacturing Practices 64 - - - -- Human and Animal Drugs Date Published: 09/19/2014 Notes:All drugs and drug products (GMP) Good Manufacturing Practices 65 - - - -- Human and Animal Drugs Date Published: 09/19/2014 Notes:All drugs and drug products (GMP) Good Manufacturing Practices 66 - - - -- Human and Animal Drugs Date Published: 09/19/2014 Notes:All drugs and drug products (GMP) Good Manufacturing Practices
  22. 22. PHARMA UPTODAY 22 Regulatory experts push for pharma cos to strengthen data integrity Regulatory experts stressed that the Indian pharma cos should put special focus on following all the data integrity requirements to avoid crackdown by regulatory agencies. This warning comes in the wake of growing incidence of issuance of letters by the US FDA and other regulatory heads to Indian pharma cos for having data integrity issues, where inspectors have discovered glaring problems in the files. Data integrity issues have become a mounting problem for the Indian pharma companies in the recent past as many like Sun Pharmaceutical have come under scan for flouting data integrity regulations. Ranbaxy, Canton Laboratories, USV Limited, Wockhardt Limited, Agila Specialties, Posh Chemicals, Aarti Drugs, Fresenius Kabi Oncology, RPG Life Sciences etc were also in the recent past issued warning letters for having incomplete records and lack of data integrity. A highly placed source from the regulatory agency informed that though data integrity had been there for a long time it is only recently that the regulatory agencies have started meticulously implementing the same. The source stressed that today violation of data integrity is seen to be as grave as violations of the GMP practices which can lead to negative observations by the regulators. ―Indian pharma companies need to be sensitised on this matter at the earliest as the statistics can threaten to impact the reputation of the industry at large. Unlike manufacturing deficiencies, data integrity issues strike at the very core of good regulation, especially since the data given stands as a proof that drugs are safe, efficacious and manufactured as per appropriate quality standards required. In fact data integrity is at the root of a number of 483s issued recently by FDA,‖ pointed out the source. Data integrity refers to maintaining, assuring the accuracy and consistency of data over its entire life-cycle and is a critical aspect to the design, implementation and usage of any product. Data integrity is one of the six fundamental components of information security and its aim is to ensure the quality of correctness, completeness, wholeness, soundness and compliance with the intention of the creators of the data. It is achieved by preventing accidental or deliberate but unauthorised insertion, modification or destruction of data in a database. Health ministry may relax rules on BA/BE studies in respect of drugs manufactured in India The Union health ministry is likely to relax rules on Bioavailability or Bioequivalence (BA/BE) studies in respect of drugs manufactured in the country. According to sources, the Drugs Consultative Committee (DCC) of the Union health ministry, which comprises all the state drug controllers besides senior health ministry officials including the DCGI, has recommended to the ministry that BA/BE studies in respect of drugs manufactured in the country should be insisted whenever there are issues relating to patient safety and variable bioavailability. ―As the infrastructure for conduct of such studies is not uniformly available in the country, it cannot be implemented as a rule‖, the DCC recommended. In the case of BA/BE studies for export purposes such studies may be permitted as per requirements. The growth of the Indian pharma industry in terms of exports is declining in the last few years and any embargo on BA/BE studies on substances discovered abroad and not marketed in India would further decline the exports. This would ultimately impact the research and drug development in the country. In
  23. 23. PHARMA UPTODAY the interest of human safety, the permission for the study may not be granted in case the well being of the trial subjects is endangered, the DCC in its meeting held recently recommended to the ministry. It however, agreed that in the case drugs which are banned in the country for marketing, the BA/BE studies should not be permitted. The DCC recommendations will now be taken up by the Drugs Technical Advisory Board (DTAB), the highest authority in the union health ministry on technical matters, which is expected to take a final call on the issue. The DCC deliberated on the recommendations of the Prof Ranjit Roy Chaudhury Committee on this issue. After detailed deliberations, the DCC asked the DTAB to consider two issues. First, the requirement of BE study for subsequent approval of new drugs already approved in the country. Presently, BE study for oral dosage form of only new drugs is required till four years of approvals of these drugs. In order to make it mandatory for all drugs other than new drugs, it would require amendment in Rules. Such a provision will also have an impact on cost, time required for grant of license, infrastructure, etc. 23 Second, continued permitting of (BA/BE) studies for export purpose. Presently, BA/BE studies of drugs of foreign manufacturer or by Indian manufacturer for generating data for submission to foreign Regulatory Authority for export purposes is being carried out at many centres in the country. The continuation of such studies for export purposes is required to be deliberated in the light of the recommendations of the Committee and its impact on the pharmaceutical industry. Apotex gets Import Alert for Bangalore Plant: Import Alert # 66-40 Published Date: 09/26/2014 Type: DWPE Import Alert Name: "Detention Without Physical Examination of Drugs From Firms Which Have Not Met Drug GMPs" Reason for Alert: *** Foreign inspections of pharmaceutical manufacturers are being performed. Detention without physical examination may be appropriate when an FDA inspection has revealed that a firm is not operating in conformity with current good manufacturing practices (GMP's). Detention without physical examination may also be appropriate when FDA receives information concerning inspections conducted by foreign or other government authorities under a Memorandum of Understanding or other agreement that FDA concludes reveals conditions or practices warranting detention of either particular products or all products manufactured by a firm. DWPE of such firms remains in effect until such time as FDA is satisfied that the appearance of a violation has been removed, either by reinspection or submission of appropriate documentation to the responsible FDA Center. *** Guidance: *** Districts may detain, without physical sampling and analysis, the indicated drug products from the foreign processors noted in the Red List of this import alert. Foreign processors listed on the Red List of this import alert who would like to request removal from that list should provide information to FDA to adequately demonstrate that the manufacturer has resolved the conditions that gave rise to the appearance of the violation, so that the agency will have confidence that future entries will be in compliance. This may include a letter detailing its corrective actions,
  24. 24. PHARMA UPTODAY accompanied by documentation. For guidance on removal from detention without physical examination, refer to FDAs Regulatory Procedures Manual, Chapter 9, "Detention Without Physical Examination (DWPE)." Information supporting removal should be sent to CDER's Office of Compliance, (HFD-300). *** 24 Product Description: Various drugs (See attachment) Charge: "The article is subject to refusal of admission pursuant to Section 801(a)(3) in that the methods and controls used in its manufacture and control of pharmaceutical products do not appear to conform to current good manufacturing practices within the meaning of Section 501(a)(2)(B)." Apotex Research Private Limited Date Published : 09/22/2014 Plot 1/2, Site #2 Bommasandra Ind. Area , 4th Phase, Jigani Link Rd., Jigani Hobli , Bangalore, Karnataka State INDIA 55 - - - -- Pharm Necess & Ctnr For Drug/Bio Date Published: 09/22/2014 Notes:Good Manufacturing Practices (GMP); 56 - - - -- Antibiotics (Human/Animal) Date Published: 09/22/2014 Notes:Good Manufacturing Practices (GMP) 60 - - - -- Human and Animal Drugs Date Published: 09/22/2014 Notes:Good Manufacturing Practices (GMP) 61 - - - -- Human and Animal Drugs Date Published: 09/22/2014 Notes:Good Manufacturing Practices (GMP) 62 - - - -- Human and Animal Drugs Date Published: 09/22/2014 Notes:Good Manufacturing Practices (GMP); These products are excluded from DWPE Riluzole tablets (62J[][]16) and Abacavir tablets (62V[][]17). 63 - - - -- Human and Animal Drugs Date Published: 09/22/2014 Notes:Good Manufacturing Practices (GMP) 64 - - - -- Human and Animal Drugs Date Published: 09/22/2014 Notes:Good Manufacturing Practices (GMP) 65 - - - -- Human and Animal Drugs Date Published: 09/22/2014 Notes:Good Manufacturing Practices (GMP) 66 - - - -- Human and Animal Drugs Date Published: 09/22/2014 Notes:Good Manufacturing Practices (GMP) Information Update - Health Canada requests quarantine of products for Canadian market from Apotex facility in Bangalore, India At Health Canada's request, Apotex Inc. will quarantine products for the Canadian market manufactured at the Apotex Research Private Limited (ARPL) facility in Bangalore, India, based on a recent import ban of products from that facility by the U.S. Food and Drug Administration (FDA). Health Canada is gathering more information, including the reasons for the FDA's actions and the potential impact of any issues it has identified on products for the Canadian market. The quarantine will allow the Department time to verify that products from this facility meet Canadian safety and quality requirements. A quarantine means the company will stop distribution of products in its possession. At this time, neither Health Canada nor the FDA has requested a recall of any products from the ARPL facility. The Department will continue to keep Canadians informed as further information becomes available.
  25. 25. PHARMA UPTODAY Health Canada last inspected the ARPL facility in February 2014 with an international regulatory partner. The visit resulted in a compliant rating. The FDA had issued a compliant rating to the same facility following its own inspection in 2013. Drug production is a global business, and Health Canada works with its international regulatory partners to monitor the manufacturing practices used to make the medicines that Canadians take. Health Canada continues to work with the FDA, other trusted international regulatory partners and the company to gather more information about the situation at the Apotex ARPL facility and the products affected. Health Canada will work with the provinces and territories to monitor the supply situation and, if necessary, develop mitigation strategies. French regulator raises concerns over Indian CRO studies Concerns over India-based GVK Biosciences have been raised in a letter from France’s ANSM (Agency for Medicines and Health Products Safety) to marketing authorization holders following a GCP (good clinical practice) inspection citing deficiencies in the CRO that stretch back to 2008. The inspection ―has raised serious concerns regarding the GCP compliance of the conduct of the clinical part of bioequivalence trials at GVK Bio, Hyderabad, India in the period July 2008 – 2014,‖ . As part of the concerns, all MAHs (marketing authorization holders) and applicants must provide information on whether the clinical part of a pivotal bioequivalence study in any of their dossiers was conducted at the CRO GVK Bio Hyderabad, India in the defined period. But ANSM notes that the enquiry is only for the clinical facility at GVK‘s Hyderabad headquarters ―and it does not concern the bioanalytical facility at the same site.‖ ANSM also requested that GVK‘s response should cover clinical activities conducted in Hyderabad, India from July 2008 onwards till the present. The company was also asked to provide information on the importance of the bioequivalence studies for dossiers submitted to national competent authorities, and on ―the potential impact on the evidence of bioequivalence mitigated by other information in the dossier.‖ GVK spokeswoman Dorothy Paul told us that the May inspection covered nine studies conducted at the Hyderabad facility that had "check-out ECGs [electrocardiograms]." Clinogent, which is the new name of GVK's clinical research business development unit, "is closely working with the authorities to resolve the queries to their satisfaction." "No decision on either rejection or approval is made yet," Paul added. Past Issues The letter comes about five years since GVK was cited for two deaths in its clinical trials, according to a study in the Indian Journal of Medical Ethics. The first case pertains to the death of an infant while being part of a trial on a pneumonia vaccine developed by Wyeth Pharmaceuticals, at St John‘s Hospital in Bangalore. The DCGI (Drug Controller General of India) eventually cancelled the trial after media reports were published. GVK, however, maintained that the infant died of an underlying condition, a serious congenital heart disease, and was not even administered the new vaccine as the child was part of the control group. The second case pertained to the death of a young adult in a Hyderabad-based facility after being subject to a bioequivalence study of the cardiac drug Felodipine. ―Here again GVK has denied any lapse on its part and claimed that the death occurred over a week after the drug was administered, by which time the drug would have been „washed out‟ of the body,”according to the Journal. ―What is particularly curious about this case is GVK‟s additional claim that the subject was a part of many other studies. The company claimed that the subject “has been participating in similar bioequivalence studies in various CROs.‘… This raises the suspicion that the deceased was a 25
  26. 26. PHARMA UPTODAY „professional‟ subject of studies and trials and was recruited after being provided monetary incentives. Not only would such a practice be unethical, it would also be dangerous given the cocktail of different drugs to which such a participant would be subjected [sic] GVK.‖ FDA Celebrates Hatch-Waxman's 30th Anniversary (easier access to cost-saving generic drugs) Thirty years ago today, President Ronald Reagan signed into law the Drug Price Competition and Patent Term Restoration Act of 1984, better known today as the Hatch-Waxman Amendments. This law, championed by Senator Orrin Hatch and Representative Henry A. Waxman, made it easier for generic drugs to enter the market, and has greatly expanded access to important—often life-saving—drugs. Over the 10-year period 2003 through 2012, generic drug use is estimated to have generated more than $1.2 trillion in savings to the health care system and to have benefitted the health and well-being of innumerable lives. Thanks to the insight of its creators, one of the strengths of this law is the fact that it provided financial incentives for pharmaceutical companies that develop and manufacture new and innovative trade name products. Under the law, sponsors of qualifying trade name drugs are provided an opportunity to extend a patent to make up for patent life lost during the process of testing and approval of the product. The law also, however, provided a clear pathway to market for generic drugs. Before Hatch-Waxman, little more than a third of branded prescription drug products even had a generic available, and those that were available were not as widely used. Today, most drugs that go off patent face competition from cost-saving generic drugs. As a result, about 85 percent of all prescriptions filled are for generic versions. 26 Importantly, while Hatch-Waxman has provided powerful cost savings for American consumers, Strides Arcolab to buy Shasun Pharma in all-stock deal Six months after the announcement of a merger of drug maker Ranbaxy Laboratories Ltd with Sun Pharmaceutical Industries Ltd, Strides Arcolab Ltd and Shasun Pharmaceuticals Ltd said on Monday that their boards have approved a scheme of merger between the two through an all stock deal to form one of the country‘s top 15 drug makers. For the merger, Shasun shareholders will receive five equity shares of Strides for every 16 shares held by them. The combination of Bangalore-based Strides and Chennai‘s Shasun creates an integrated pharma company of scale with strong presence in branded generic formulations and active ingredients segments with a combined sales of Rs.2,500 crore. The other strengths will include a portfolio of some 100 products, 12 manufacturing facilities including six US Food and Drug Administration-approved factories and a combined research team of 400 people. The rationale for the merger, according to the companies, is significant de-risking of business and synergistic opportunities in operations and cost savings through economies of scale. The combined entity will leverage Shasun‘s active ingredient manufacturing capacities and shift focus towards niche or difficult to make pharma inputs along with finished dosages portfolio and pipeline, the companies said in a joint statement on Monday.
  27. 27. PHARMA UPTODAY ―Since the divestment of our injectables business, which resulted in significant value creation for our shareholders, Strides has refocused on its oral finished formulation business,‖ said Arun Kumar, founder and group chief executive officer of Strides Arcolab. He added that the merger of Shasun accelerates the company‘s strategy and growth prospects by creating a larger scale, fully integrated, leading Indian pharma company with multiple growth drivers and synergies that will allow for enhanced profitability and more efficient use of the combined infrastructure and enhanced value creation opportunities for the combined shareholder group. Shasun chief executive and managing director Abhaya Kumar said, ―Strides and Shasun bring complementary strengths and shared values of developing products and market opportunities across geographies and the combination accelerates both scale and scope.‖ ―We are confident that the vertically integrated new combination will deliver further additional value in the near term for all stakeholders above and beyond the strong gains we have achieved to date on our own,‖ he added. FDA warns consumers not to use Eu Yan Sang (Hong Kong) Ltd.’s “Bo Ying compound" The U.S. Food and Drug Administration warns parents and caregivers not to use ―Bo Ying compound‖ manufactured by Eu Yan Sang (Hong Kong) Ltd. due to the potential lead poisoning risk associated with the product. The powdered product is marketed in retail outlets and online for use in infants and children for treatment of a variety of conditions including influenza, fever, sneezing, and nasal discharge. The product is labeled in Chinese and English. Parents and caregivers are advised to not purchase or use this product. Anyone using this product or providing it to a child should immediately consult a health care professional. Exposure to lead can cause serious damage to the central nervous system, the kidneys, and the immune system. In children, chronic exposure to lead, even at low levels, is associated with impaired cognitive function, including reduced IQ, behavioral difficulties, and other problems. FDA learned of this risk from the New York City Department of Health & Mental Hygiene after the product was tested and found to contain high levels of lead. FDA has received one adverse event report of lead poisoning in an 18-month-old child who was given this product. Health care professionals and consumers are encouraged to report to FDA any adverse events potentially related to ―Bo Ying compound‖ manufactured by Eu Yan Sang (Hong Kong) Ltd. or to any other alternative medicines to FDA‘s MedWatch Adverse Event Reporting program by: 27 o Completing and submitting the report online at MedWatch Online Voluntary Reporting Form o Downloading and completing the form, then submitting it via fax at 1-800-FDA-0178 EMA opens investigation into India’s GVK Bio over ECG falsifications At the request of the European Commission, the EMA (European Medicines Agency)announced Friday that it would open a review into findings that GVK Biosciences’ site in Hyderabad, India falsified electrocardiograms in all nine clinical trials evaluated. The investigation follows an inspection by the French regulator ANSM at the Indian CRO (contract research organization), which raised concerns about study data dating back to July 2008 used to support the marketing authorisation applications of generic medicines. ANSM sent a letter to marketing authorization holders with regard to the use of GVK BIO‘s clinical facility in Hyderabad, India. A GVK spokeswoman previously told us that the ANSM inspection involved the use of ECGs.
  28. 28. PHARMA UPTODAY But Sabine Jülicher, Head of Unit, Medicinal products – authorisations at the EMA, cited a number of ANSM‘s findings in a letter to CHMP, including: ―falsifications of electrocardiograms were detected in each and every one of the 9 trials inspected by the ANSM.‖ ―The falsification of these ECGs was performed by at least 10 different individuals. The falsifications took place between at least July 2008 and 2013…the systematic nature of the falsifications of electrocardiograms, the extended period of time during which they took place and the number of members of staff involved highlight critical deficiencies in the quality system in place at GVK Bio's clinic in Hyderabad,‖ Jülicher writes. ―They also show a lack of GCP training, awareness and understanding of members of GVK Bio staff, a lack of understanding by them of the importance of data integrity and of the possible consequences of their acts, as well as a lack of overview of clinical trial activities by the investigators,” she says. ―The seriousness of the deficiencies identified and the lack of GCP compliance at GVK Bio's clinic in Hyderabad raise questions as to the acceptability of the clinical part of all other bioequivalence trials performed at that site in support of marketing authorisations applications.‖ EMA Action The EMA‘s Committee for Medicinal Products for Human Use (CHMP) will now review available data to determine which medicines are affected by the inspection findings and issue a recommendation on whether their marketing authorisations should be maintained, varied, suspended or withdrawn across the EU. GVK spokeswoman Dorothy Paul told us: "This is a natural next step as per referral procedure initiated by EMA as a follow up of ANSM inspection." GVK action EMA requests that GVK respond in writing several questions, including: ―Discuss the root cause of this issue affecting the GVK Biosciences-Hyderabad site and provide assurance that these issues‖ are confined to the Hyderabad site from July 2008 to present. In addition, the European regulator calls on GVK to ―indicate which measures have been undertaken to investigate if this is a corporate issue.‖ As far as a timeline, GVK has until Oct. 3 to respond. Between Oct. 13-23, the EMA rapporteur and co-rapporteurs‘ assessment reports will be circulated to CHMP, which will offer comments and then update 28 the reports. A list of outstanding issues and CHMP discussion will begin on Oct. 23. WHO releases 33rd edition List of Prequalified Quality Control Laboratories For details browse: http://apps.who.int/prequal/lists/PQ_QCLabsList.pdf
  29. 29. PHARMA UPTODAY 29 FDA Form 482: FDA 482 - called "Notice of inspection"  FDA Investigators must formally identify themselves by presenting credentials  FDA issues a FDA 482- to Inspection Coordinator/Executive Manager  A copy shall be obtained for the Inspection File  Firm can not copy FDA credentials FDA Form 483: An FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgement may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts. FDA investigators are trained to ensure that each observation noted on the FDA Form 483 is clear, specific and significant. Observations are made when in the investigator’s judgement, conditions or practices observed would indicate that any food, drug, device or cosmetic has been adulterated or is being prepared, packed, or held under conditions whereby it may become adulterated or rendered injurious to health. FDA Form 484: FDA inspectors can collect samples from the site but they have to issue a receipt of samples. Items not requiring a FDA 484  Items or Materials Examined but not removed  Labels or Promotional Material  Photographs  Records
  30. 30. PHARMA UPTODAY 30 New Guidance Guidance for Industry: Electronic Submission of Lot Distribution Reports This guidance provides you, licensed manufacturers of products distributed under an approved biologics license application (BLA) (henceforth referred to as applicants), with recommendations on how to submit lot distribution reports (LDRs) for biological products in an electronic format that FDA can process, review, and archive. FDA‘s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe FDA‘s current thinking on a topic, and should be viewed only as recommendations unless specific regulatory or statutory requirements are cited. The use of the word should in FDA‘s guidances means that something is suggested or recommended, but not required. Source: http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInforma tion/Guidances/General/UCM412006.pdf Manual of Policies and Procedures (MAPP) 4190.1 rev. 2 Drug Shortage Management This MAPP establishes CDER‘s procedures for notification, evaluation, and management of drug shortage situations for all CDER products including those studied or marketed under investigational new drug applications (INDs), new drug applications (NDAs), biologics license applications (BLAs), abbreviated new drug applications (ANDAs), and unapproved drugs marketed without an approved application. This MAPP also outlines the responsibilities of the CDER Drug Shortage Staff (DSS). This MAPP does not establish procedures for interactions between CDER and other FDA centers or offices outside of CDER, with the exception of FDA‘s Office of Regulatory Affairs (ORA). Source : http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ ManualofPoliciesProcedures/UCM079936.pdf Manual of Policies and Procedures (MAPP) Communicating Drug Approval Information This MAPP establishes procedures for clearing and publishing new drug application (NDA), biologic license application (BLA), and abbreviated new drug application (ANDA) approval information on CDER‘s Web site. The approval or tentative approval of drug applications is of interest both inside and outside of FDA. FDA district offices, the trade press, the pharmaceutical industry, individual
  31. 31. PHARMA UPTODAY practitioners, patients, and international FDA counterparts are interested in this information. When an application is approved, FDA makes the information available according to the priorities and time periods specified in this MAPP. Source: http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/ CDER/ManualofPoliciesProcedures/UCM078818.pdf 31 TGA Releases New Guidance 23: Nonclinical studies Previously ARGPM Appendix 23: Supplementary non-clinical guidelines 15 September 2014 Introduction This guidance is to assist sponsors with submitting nonclinical studies in Module 4 of the Common Technical Document (CTD) as part of the application to register a prescription medicine on the Australian Register of Therapeutic Goods (ARTG). This guidance is in addition to the adopted European Union (EU) guidelines for nonclinical studies. The submitted additional information should include:  All relevant nonclinical information, whether favourable or unfavourable to the medicine.  Details of any incomplete or abandoned pharmacological or toxicological testing, as well as individual animal data from toxicity studies. Contents  Additional pharmacodynamic and pharmacokinetic studies  Additional toxicology studies  Excipients  Version history 23.1 Additional pharmacodynamic and pharmacokinetic studies 23.1.1 Pharmacodynamics  Establish, where possible, the mechanism of the primary pharmacological action.  Investigate, where relevant, the pharmacology of significant metabolites. 23.1.2 Pharmacokinetics These notes are concerned with the time course of the absorption, distribution and excretion of new medicinal products and with their metabolism in relation to their safety. Data on the levels of substance and metabolites in blood, body fluids, organs and in the excreta can be obtained by physical, chemical or biological methods. When a labelled substance is used, the position of the label in the molecule and the specific activity of the material must be stated. Consideration should be given when selecting the position of the label to its likely metabolic fate. Attention must be given to the fact that the measured label in body fluids may not correspond to that of the unmodified substance, but may include labelled metabolites and conjugates. Attention should be given to the possibility of isotope exchange with endogenous compounds. The animal species in these studies usually should be those used in the pharmacological and toxicological investigations. A preliminary study of kinetics and metabolism of the medicinal product in a few human subjects could provide useful information in choosing the animal species to be used in repeated dose toxicity studies.
  32. 32. PHARMA UPTODAY 32 Information should be presented on the following items:  Absorption (fractional absorption, kinetics)  Distribution in the principal organs and tissues and the time course in body fluids  Blood, plasma or serum half-life  Plasma protein binding  Characterisation of the pattern of metabolites in excreta, and where practicable, identification of major metabolites  Route and time course of excretion of substance and metabolites  If biliary excretion is a major route of elimination , then the possibility of enterohepatic recycling should be investigated. A quantitative account of the fate of the administered dose should be attempted. To assist in the interpretation of toxicological studies, it is important to compare the exposure of the animals used in the toxicity testing with the anticipated exposure in patients under the proposed therapeutic dose regimen.  Provide systemic exposure data for all animal species used in repeat dose, carcinogenicity and reproductive toxicity studies.  Provide exposure data in humans at the maximum recommended dose (including, where relevant, paediatric exposure data).  Include tables comparing these data as part of the Nonclinical Summary or Overview  Ensure the exposure data, preferably obtained from the toxicity studies, include: o the Cmax (after a single dose and at steady state) and area under the curve (AUC) data for the parentdrug and all major active metabolites, and/or o major pharmacologically inactive metabolites of potential toxicological significance.  Include plasma protein binding data and assay methodology, if there are notable binding differences between nonclinical and clinical studies. 23.2 Additional toxicology studies 23.2.1 Specialised investigations In addition to the standard investigations, special investigations for specific toxicological effects may be necessary to adequately assess safety of medicines that show specific toxicities such as:  neurotoxicity  cardiovascular toxicity  hepatotoxicity  immunotoxicity  phototoxicity  ocular toxicity For therapies involving long-term administration:  Include repeat-dose toxicity studies of six months duration in rodents and nine months in nonrodents. Shorter duration toxicity studies may be appropriate in particular circumstances, such as where: o intermittent administration would result in exposure of short periods (e.g. medicines for migraine) o the intended patients have a short life expectancy (e.g. medicines for advanced cancer)
  33. 33. PHARMA UPTODAY 33 o immunogenicity or intolerance confounds the conduct of longer term studies. Sponsors are encouraged to investigate:  the possible mechanism(s) underlying the changes observed in toxicity studies  the potential reversibility of toxic changes seen in the repeat-dose studies. 23.3 Excipients For excipients used for the first time in a medicine:  Investigate the toxicology of the excipient as if it were a new drug substance. For excipients already approved in a medicine registered in Australia:  Provide additional nonclinical data for either: o a new route of administration o an increased daily dose o an increased strength. For excipients that are well documented or described in a default standard pharmacopoeia, but not previously used in a medicine in Australia:  Provide adequate data to justify the use of such excipients. This may include published material.  Nonclinical data may also be required if the default standard does not contain sufficiently specific impurity controls to ensure that potentially toxic impurities arising from a modified or different route of synthesis are adequately controlled. Complaints and Recalls: new EU-GMP Chapter 8 published The European Commission has published the final Chapter 8 of the EU Guidelines for GMP (Complaints, Quality Defects and Product Recalls). The chapter has been revised completely. Whereas the current one has less than two pages focusing on complaints and recalls only, the revision is six pages long, defining expectations for:  Personnel and Organisation  Procedures for handling and investigating complaints including possible quality defects  Investigation and Decision Making  Root Cause Analysis and Corrective and Preventative Actions  Product Recalls and other potential risk-reducing actions Throughout its chapters, the new version of Chapter 8 introduces Quality Risk Management principles and appropriate root cause analysis work when investigating quality defects and complaints. The scope includes complaints including quality defects (this is also new) and recall issues with respect to marketed medicinal products and investigational medicinal products (IMPs) that have been released to clinical trials. The new chapter 8 is better aligned with the wording of Directive 2003/94/EC with regard to when a quality defect/complaint should be reported to the competent authority.
  34. 34. PHARMA UPTODAY Besides investigating and determining the cause(s) of quality defects/complaints, the revised chapter 8 also wants to ensure that appropriate corrective and preventative actions are put in place to avoid recurrence of the issue. CAPA has already been introduced in the revision of chapter 1 and is now also be recognised in chapter 8. The effectiveness "should be monitored and assessed". When it comes to product recalls, the new chapter also addresses risk mitigation and risk-based thinking into the recall decision-making process. In this context, the Manufacturer and Marketing Authorisation Holder shall ensure continuity of supply for critical medicinal products where alternative products may not be readily available. Consultation with the Competent Authority is inevitable. The Qualified Person (QP) who is involved in the certification for release of the concerned product will play an important role. If the QP is not directly responsible for managing complaint and quality defect investigations and for deciding the measures to be taken, he or she "should be made formally aware of any investigations, any risk-reducing actions and any recall operations, in a timely manner". For all respective actions like for example handling, reviewing and investigating complaints, sufficient personnel and resources should be made available. The revised chapter details the requirements for written procedures like SOPs. They should at least address the following: 34  The description of the reported quality defect.  The determination of the extent of the quality defect.  Handling of samples  The assessment of the risk(s) posed by the quality defect.  How decisions and assessments are made  Notification to the relevant authorities and other internal and external communications  Root cause analysis and CAPAs. There should also be established written procedures in relation to recall activities or the implementation of any other risk-reducing actions, so that recall operations can be initiated promptly and at any time. So called Mock Recalls are now also described in more detail. Evaluations of the effectiveness "should extend to both within office-hour situations as well as out-of-office hour situations and, when performing such evaluations, consideration should be given as to whether mock-recall actions should be performed. This evaluation should be documented and justified. " Overall, the goal is to achieve information-based and scientific decisions in relation to risk-mitigating actions. It should also be highlighted that there may be more than one cause associated with a quality defect/complaint. However all likely causes should be thoroughly investigated leading to more effective preventative actions being identified and put in place. FDA publishes ICH Q4B - Annex 6 on Uniformity of Dosage Units On 16 June 2014, the FDA published the ICH harmonised Guideline entitled "Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Uniformity of Dosage Units General Chapter (Q4B Annex 6)". This ICH Guideline thus came into force in the USA, too. The objective of the ICH Q4B Working Group is to reach mutual recognition by regulatory authorities in the ICH regions for all testing methods listed in the ICH Q6A Guideline on Specifications. Through this,

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