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Pharma Uptoday Monthly Magazine - Volume 11, Issue Feb 2015

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3 News Uptoday

35 New Guidance

42 Audit Findings
483 Observations
- Top Drug 483 Observations

46 EMA Non-Compliance Reports

- Wockhardt Limited, Aurangabad
- AGEPHA, Austria
- North China Pharmaceutical Group Semisyntech Co., Ltd, China

48 Regulations of the Month

- § 211.188 Batch production and control records
- § 211.192 Production record review
- § 211.194 Laboratory records.

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Pharma Uptoday Monthly Magazine - Volume 11, Issue Feb 2015

  1. 1. VOLUME: 11 - ISSUE: FEB 2015 | PHARMA UPTODAY For feedback, suggestions & queries write to us on “pharmauptoday@gmail.com”
  2. 2. PHARMA UPTODAY 2 Inside this issue 3 News Uptoday 35 New Guidance 42 Audit Findings 483 Observations - Top Drug 483 Observations 46 EMA Non-Compliance Reports - Wockhardt Limited, Aurangabad - AGEPHA, Austria - North China Pharmaceutical Group Semisyntech Co., Ltd, China 48 Regulations of the Month - § 211.188 Batch production and control records - § 211.192 Production record review - § 211.194 Laboratory records.
  3. 3. PHARMA UPTODAY 3 News Uptoday Canada Hits Dr. Reddy’s With Import Ban Indian drug manufacturers are now coming under tough scrutiny of Canadian drug regulators. Health Canada this week stated that Canadian importers of drugs are putting an import ban on drug products from Dr. Reddy‘s Laboratories, as well as IPCA Laboratories. Health Canada stated that Canadian drug importers are quarantining health care products from these two companies, due to concerns about data integrity. The Canadian regulator stated that there are concerns being raised about the reliability of lab data that is coming from several sites of these firms. This action applies to APIs that come from Dr Reddy‘s labs and also finished drug products. Only a few months ago, Health Canada also took actions against IPCA Lab, which raised worries about the reliability of their data pertaining to safety and quality issues. The Srikakulam plant at Dr Reddy‘s and the Pithampur facility for IPCA lab have both been criticized by FDA in recent months. Both of them got a 483 in 2014 that focused on nine serious observations. In July 2014, IPCA stopped sending out drug shipments and APIs from its facility in Ratlam India after an FDA audit raised serious quality concerns on an FDA 483. It added that the decision would have an effect upon the formulations that it exports to the US. It remains to be seen how much this ban will affect the bottom line for Dr Reddy. Much depends upon how quickly the company is able to fix its quality problems. Recall: Valeant Pharmaceutical North America LLC Issues Voluntary Nationwide Recall of Virazole® (Ribavirin Powder For Solution) Due to Microbial Contamination Inhalation of a non-sterile product with microbial contamination into the airways could increase the risk of respiratory infection. The risk is higher in patients who are immunocompromised (because of underlying disease), and are more susceptible. Virazole is indicated for the treatment of hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus (RSV). Valeant has not received reports of adverse events or injuries, related to this recall. Virazole is packaged in 100 mL, 6 g Vial, 4-pack NDC 00187-0007-14 which is to be reconstituted with 300 mL Sterile Water for Injection or Sterile Water for Inhalation (no preservatives added) and administered only by a small particle aerosol generator (SPAG-2). The affected Virazole lot is Lot No. 340353F with an expiration date of Oct-2018. Virazole was distributed in the U.S. and Australia.
  4. 4. PHARMA UPTODAY 4 VPNA is notifying its distributors and customers by mail and is arranging for return of all recalled product of this lot. This recall only affects this lot of Virazole; all other lots are not affected and are not involved in this recall. Customers with questions regarding this recall can contact VPNA by phone at 800-321-4576 Monday - Friday, 8am - 5pm (Eastern) or by e-mail address at pharmcs@valeant.com. Consumers should contact their physician or healthcare provider for questions regarding this product. Adverse reactions or quality problems experienced with the use of this product may be reported to VPNA at 877-361-2719 or to the FDA's MedWatch Adverse Event Reporting program as follows:  Complete and submit the report Online: www.fda.gov/medwatch/report.htm  Regular Mail or Fax: Download form www.fda.gov/MedWatch/getforms.htm or call 1-800- 332-1088 to request a reporting form, then complete and return to the address on the pre- addressed form, or submit by fax to 1-800-FDA-0178 This recall is being conducted in conjunction with the U.S. Food and Drug Administration. About Valeant Pharmaceuticals North America LLC: Valeant Pharmaceuticals North America LLC, is a specialty pharmaceutical company that develops, manufactures and markets a broad range of pharmaceutical products primarily in the areas of dermatology, eye health, consumer healthcare and other pharmaceutical products. More information about Valeant can be found at www.valeant.com. US, EU drug approvals soared in 2014 The US Food and Drug Administration and the European Medicines Agency have both reported high levels of new drug approvals in 2014. The US FDA approved a total of 41 new Molecular Entities (NMEs) and Biologic License Applications (BLAs) last year, 14 more than it did in 2013. This is also the second-highest total after the record 53 approvals announced by the agency during 1996. The final approval of last year was for Bristol-Myers Squibb‘s Opdivo (nivolumab), for the treatment of unresectable or metastatic melanoma who no longer respond to other drugs, announced on December 22, while the year‘s first approval, on January 8, was also for a Bristol-Myers Squibb product – Farxiga (dapaglifozin), used to improve glycemic control, along with diet and exercise, in adults with type 2 diabetes. Alogether, the FDA approved nine treatments for cancer in 2014, the others being: AstraZeneca‘s Lynparza (olaparib) for advanced ovarian cancer; Amgen‘s Blincyto (blinatumomab), to treat patients with Philadelphia chromosome-negative precursor B-cell acute
  5. 5. PHARMA UPTODAY 5 lymphoblastic leukemia (B-cell ALL); Merck & Co‘s Keytruda (pembrolizumab), for patients with advanced or unresectable melanoma who are no longer responding to other drugs; Gilead Sciences‘ Zydelig (idelalisib) used in three types of blood cancers; Spectrum Pharmaceuticals‘ Beleodaq (belinostat) for the treatment of peripheral T-cell lymphoma (PTCL); Novartis‘ Zykadia (certinib) for late-stage lung cancer; Janssen Biotech‘s Sylvant (siltuximab) for multicentric Castleman‘s disease (MCD), a rare disorder similar to lymphoma; and Eli Lilly‘s Cyramza (ramucirumab) for stomach cancer. Another cancer-related approval was for Eisai‘s Akynzeo (netupitant and palonosetron), to treat nausea and vomiting in patients undergoing cancer chemotherapy. Meantime, the EMA reports that it recommended 82 new products last year – a total which includes generics – compared to 79 in 2013 and 57 the year before. Last year, EMA received 118 applications for initial marketing authorisations (MAs) and for 2015 it says it expects a similar number, at 114. More than 20% of these applications are forecast to be for treatments for rare diseases – these numbered 23 in 2014 and are expected to total 24 during the current year. The Agency also says it is expecting a general increase in pre-authorisation activities in human- use medicines this year. In particular, it is forecasting a sustained increase in requests for scientific advice on clinical development, including parallel advice with health technology assessment (HTA) bodies, with the aim of facilitating timely access to medicines for patients. Health Canada: Health products from Sri Krishna Pharmaceuticals quarantined due to data integrity concerns Starting date: January 6, 2015 Posting date: January 6, 2015 Type of communication: Information Update Subcategory: Drugs Source of recall: Health Canada Issue: Important Safety Information Audience: General Public Identification number: RA-43209 Issue At Health Canada's request, Canadian importers have agreed to quarantine health products made with active pharmaceutical ingredients (APIs) from Sri Krishna Pharmaceuticals Ltd. in Hyderabad, India, due to data integrity concerns.
  6. 6. PHARMA UPTODAY 6 This action comes in light of recent information from trusted regulatory partners that raised concerns about the reliability of the laboratory data generated at this site. Health Canada is taking this action as an interim precautionary measure to help mitigate any potential risk. A quarantine means that the Canadian importers and distributors have agreed to stop distributing APIs or finished dosage form products containing active ingredients from this site. At this time there is no identified risk to health, and Health Canada is not requesting a recall of any of the products. Health Canada's action applies to APIs from Sri Krishna Pharmaceuticals, which are used to make finished drug products that are sold to consumers. Health Canada has compiled an initial list of products affected by the quarantine. The list will be updated as new information becomes available. Any medically necessary products will undergo appropriate testing to address any potential safety concerns. Health Canada will continue to work with international partners and Canadian importers to gather and assess information regarding the situation and take action as necessary to help protect Canadians. Canadians should not make any changes to their medication without first consulting with a healthcare professional. Health Canada has engaged provinces and territories to share information about the situation. The Department will also continue to keep Canadians informed as new information becomes available. Number of 483 issued from the System in 2014 (10/1/2013 to 9/30/2014) Center Name 483 issued Foods 2476 Devices 972 Drugs 645 Veterinary medicine 337 Bioresearch monitoring 297 Biologics 146 Human tissue for transplantation 115 Parts 1240 and 1250 70 Radiological health 16 Sum Product Area 483s from System* 5074 Actual Total in system 483s** 4943
  7. 7. PHARMA UPTODAY 7 Top 10 Inspections 483 Observations of 2014 related to Drugs: Cit e Id Reference Number Short Description Long Description Frequenc y 110 5 21 CFR 211.22(d) Procedures not in writing, fully followed The responsibilities and procedures applicable to the quality control unit are not [in writing] [fully followed]. Specifically, *** 145 360 3 21 CFR 211.160(b) Scientifically sound laboratory controls Laboratory controls do not include the establishment of scientifically sound and appropriate [specifications] [standards] [sampling plans] [test procedures] designed to assure that [components] [drug product containers] [closures] [in- process materials] [labeling] [drug products] conform to appropriate standards of identity, strength, quality and purity. Specifically, *** 109 202 7 21 CFR 211.192 Investigations of discrepancies, failures There is a failure to thoroughly review [any unexplained discrepancy] [the failure of a batch or any of its components to meet any of its specifications] whether or not the batch has been already distributed. Specifically, *** 94 136 1 21 CFR 211.100(a) Absence of Written Procedures There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Specifically, *** 87 121 5 21 CFR 211.67(b) Written procedures not established/followed Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product. Specifically, *** 72 145 1 21 CFR 211.113(b) Procedures for sterile drug products Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not [established] [written] [followed]. Specifically, *** 72
  8. 8. PHARMA UPTODAY 8 188 3 21 CFR 211.165(a) Testing and release for distribution Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the [final specifications] [identity and strength of each active ingredient] prior to release. Specifically, *** 64 121 3 21 CFR 211.67(a) Cleaning / Sanitizing / Maintenance Equipment and utensils are not [cleaned] [maintained] [sanitized] at appropriate intervals to prevent [malfunctions] [contamination] that would alter the safety, identity, strength, quality or purity of the drug product. Specifically, *** 63 127 4 21 CFR 211.68(a) Calibration/Inspection/C hecking not done Routine [calibration] [inspection] [checking] of [automatic] [mechanical] [electronic] equipment is not performed according to a written program designed to assure proper performance. Specifically, *** 54 191 4 21 CFR 211.166(a) Lack of written stability program There is no written testing program designed to assess the stability characteristics of drug products. Specifically, *** Drug manufacturing industry cries foul over poor regulation India's drug manufacturing industry is afflicted with poor regulation - a case of authorities not scaling up the supervisory process to match the pace of the sector's growth. The botched up sterilisation surgeries in Chhattisgarh in November, which left 13 women dead, was a grim reminder about the need to increase oversight of both health practices in the country as well the manufacture of drugs by companies, some of which face increasing scrutiny for allegedly not adhering to global regulatory practices.
  9. 9. PHARMA UPTODAY 9 While drug makers say local regulators are ill-equipped and inadequately staffed to monitor them, the watchdogs in turn hold state governments responsible for failing to strengthen the supervisory mechanism."The governments were in a mad rush to attract investments by creating tax havens but did not pay enough attention to augment the scrutiny machinery. As a result, drug regulators and manufacturers in very few states could attain respectable quality standards," a state drug controller told on condition of anonymity, admitting inadequacies in the system. Both the central and state government are involved in granting approvals to drugs and their manufacture. Central government authorities approve clinical trials and new drugs, apart from controlling imports and prescribing standards. States issue manufacturing and sales licenses and carry out plant inspections. However, drug controllers appointed by the state governments are hardly equipped with laboratories for quality controls and checks. "It is well recognised that the states have to strengthen their regulatory setup, undertake capacity building and bring in transparency and accountability in the administration. The Centre has offered to contribute 75% of these costs, but the action lies with the states," Indian Pharmaceutical Alliance director general DG Shah said. In 2003, a committee headed by RA Mashelkar appointed to study drug regulatory preparedness and spurious drugs had pointed out that only a few states have well-equipped testing laboratories, while others either have no laboratory or a very small one, with limited testing facilities. "The states have not taken action to provide full-fledged testing facilities, despite the rapid increase in the number of sales premises. The number of drug inspectors in the states, as also their skills, are observed to be generally not commensurate with the load of work of inspections and monitoring of quality of drugs," the panel said. As against about 20,000 pharmaceutical manufacturers, traders and services firms in the country, the Central Drugs Standards Control Organization has less than 300 staff to grant drug
  10. 10. PHARMA UPTODAY 10 approvals and all the state drug controllers together have about 1,000 inspectors to regulate them, a senior CDSCO officials said. "Though the Union government had agreed to give us at least 1,200 more regular staff and another 1,200 staff on contract basis, we are still waiting for funds and clearances. The central drug laboratories are poorly equipped with testing infrastructure and personnel," the official said. Insisting on the urgent need to evolve a sound and unified drug control framework across nations and states, the Indian Pharmaceutical Congress has convened a three-day global conference of regulators and manufacturers in Hyderabad from January 23, said its organising committee chairman Ravi Udayabhaskar. In the case of the sterilisation deaths, the manufacturing licenses of two firms - Mahawar Pharma in Chhattisgarh and Technical Lab & Pharma in Uttarakhand - were temporarily suspended based on preliminary reports of the Central Drugs Laboratory in Kolkata. Both the drug makers denied that their products caused the deaths. Source: economictimes.indiatimes.com/ China to allow online sales of prescription drugs as early as this month: sources China will allow online sales of prescription drugs as early as this month, a policy that will open up an over 1 trillionyuan ($161 billion) market to online pharmacy operators like Alibaba Group Holding Ltd and Wal-Mart Stores Inc. The China Food and Drug Administration (CFDA) is finalising which prescription medicines to approve for sale, a senior healthcare policy adviser told Reuters. The policy would help reform a fragmented and opaque market controlled by state-run distributors and hospitals, brought into the spotlight last year by a bribery case which saw drugmakerGlaxoSmithKline PLC fined nearly $500 million. "The policy will be released in January or February and the CFDA is actively working on it," said the adviser, who was not authorised to speak with media on the matter and so declined to be identified. Hospitals currently account for around 70 percent of drugs sold to consumers. Among retailers, online pharmacies are restricted to selling over-the-counter medicines and healthcare products such as cough remedies and vitamin tablets. The new policy could eventually allow online retail pharmacies such as Alibaba HealthInformation Technology Ltd and the pharmacy platform of JD.com Inc to wrest sales from hospitals. Frank Zhao, chief financial officer at pharmacy chain China Jo-Jo Drugstores Inc, said the CFDA had was reviewing the list of prescription drugs for sale online. "It may be a couple of days or weeks before the final list," he said.
  11. 11. PHARMA UPTODAY 11 ONLINE WINNERS Pharmacies with an online presence, such as U.S.-listed Jo-Jo Drugstores and ChinaNepstar Chain Drugstore Ltd, as well as general online retailers also stand to benefit. Marketplaces Alibaba and JD.com already have licences to sell over-the-counter drugs online, as does U.S. retailer Wal-Mart. Initially, online prescription drug sales are likely to be business-to-business (B2B) before spreading to retailers. The potential size of the B2B drug market ranges from 300 billion yuan to as much as 800 billion yuan, according to Deutsche Bank. At risk could be offline middlemen such as Sinopharm Group Co Ltd, Shanghai Pharmaceuticals and China Medical Systems Holdings Ltd. It will take considerable time for companies and consumers to get used to the new model, said Jo-Jo Drugstores' Zhao, adding the policy would allow his firm to expand significantly online. In the U.S., around a third of drugs are sold online compared with almost zero currently in China, Zhao said. Drugs sold online may be up to 10 percent cheaper than those sold through traditional channels, analysts say. "The government has a common theme - to improve quality of care for the masses and at the same time contain costs," said Andrew Chen, head of PwC's China Consulting Healthcare practice. "So, the e-pharmacy side is definitely going to be a trend." ($1 = 6.2092 Chinese yuan renminbi) Source: http://www.reuters.com/ Why has FDAIssued so few Warning Letters About Drug Marketing? Despite the proliferation of media and pharmaceutical marketing, the FDA office that monitors prescription drug promotions has consistently issued fewer infraction letters over the past decade. But last year reached a new low – just 10 were issued to drug makers. Over the past decade, the FDA Office of Prescription Drug Promotion generally sent between 20 and 30 letters to drug makers each year, although 52 were issued in 2010. However, more than 100 letters were issued between 1997 and 1999. The output reached a peak in 1998, when 156 were sent to companies, shortly after the FDA expanded direct-to-consumer advertising. Why was there a gradual decline and, in particular, a meager amount last year? Mark Senak of the Fleishman-Hillard public relations firm, who writes the Eye on FDA blog and first noticed this trend, speculates that, ―depending on your point of view, you could say [the FDA] has either stopped looking for violations or industry has gotten really proficient at communicating within regulatory parameters.‖
  12. 12. PHARMA UPTODAY 12 One might think that, with the advent of the Internet and the subsequent proliferation of prescription drug marketing, the FDA might have found a rising number of promotional infractions in recent years. However, as Senak notes, the agency has been rather slow to issue draft guidances for how drug makers should be using social media. It was only last June, in fact, that the FDA took this step, five years after signaling its intention. Although drug makers use the Internet to engage consumers in varying degrees, the lack of more specific guidance has slowed their efforts to embrace this as a marketing tool. We asked the FDA for comment and will update you accordingly. One of those draft guidances, by the way, offers instructions on how companies should attempt to correct product information on websites that are run by others, such as chat rooms. The other addresses how products, including risk and benefit information, can be discussed in venues such as Twitter, as well as paid search links on Google and Yahoo. Indian pharma’s lack of investigations & appropriate lab systems lead to poor quality metrics standards: AG Raghu Inadequate investigations, lack of appropriate laboratory systems, repeat issues due to improper implementation of corrective and preventive action (CAPA) have now indicated the need to implement quality metrics, according to AG Raghu, technical director, Gland Chemicals. Regular monitoring of quality metrics at production plants and R&D labs leads to continuous improvement, he said. Traditionally, the pharmaceutical industry is a highly regulated environment with little flexibility in which regulators have taken the responsibility for product quality. However, there still exists blind compliance mentality resulting in variability of production batches. This is because the manufacturers are focussed on delivering high quality drugs and limited focus on process understanding. This calls for the industry to rework on rejects, Raghu said at the recently concluded ISPE event. Specific parameters that will be continuously monitored by quality department that are considered to be key indicators of the quality, as well as the effectiveness of the GMP systems are the laboratory, production, materials, packaging and labelling, facilities and equipment, he said. Innovations and improvement have been constrained due to inflexible regulatory environment and focus on compliance not science. Now with a string of warning letters, pharmaceutical
  13. 13. PHARMA UPTODAY 13 industry is in a microscopic scrutiny by global regulators. The US Food and Drug Administration Safety and Innovation Act (USFDASIA) mandates implementation of a risk-based inspection program. A survey conducted by the International Society for Pharmaceutical Engineering (ISPE) also indicates quality problems are the most common cause of drug shortages, accounting for nearly 46 per cent of all drug shortages. ISPE proposed to focus any further activity on manufacturing and quality issues . The survey report identified metrics to detect and address shortages as a potential improvement opportunity, he said. Strategies to assess and adopt appropriate quality or other alerting metrics within the pharma industry would prove to be a critical aspect to prevent or mitigate future drug shortages, he pointed out. ISPE has established a quality metrics project with the following goal to produce a ―whitepaper‖ acceptable to industry on quality metrics, which could be reportable to the FDA to support a risk-based inspection programme included in Sections 704 to706 of USFDASIA. An objective measure of the quality of a product or process makes considerable relevance to patient recovery. This is where the need to measure the quality of a pharma production site is of utmost importance, because it measures the ability of the facility to manufacture products fit for intended use. Therefore quality metrics evaluation should be employed as part of management process to ensure maintenance of an effective system. There is also the need to create cross functional teams, said the Gland Pharma technical director. EU DCP: International collaboration for the evaluation of generic drugs International Generic Drug Regulators Programme (IGDRP) Information Sharing Pilot to be extended to generics authorised through the EU centralised procedure The TGA is participating in an international collaboration programme led by the European Union (EU) under the auspices of the IGDRP through which, upon request from a generic pharmaceutical company, the assessment reports generated as part of EU Marketing Authorisation procedures will be shared in real time with collaborating regulatory agencies outside the EU such as the TGA. The IGDRP was launched in April 2012 with the aim of regulatory agencies to pursue collaboration and convergence to mitigate challenges of worldwide generic global development
  14. 14. PHARMA UPTODAY 14 and approval programs. As part of the IGDRP, an information sharing pilot has been initiated in July 2014 using the European Union's Decentralised Procedure (DCP) as a model for the sharing of information during the scientific assessment phases of the DCP with IGDPR non-EU agencies, including the TGA. It has now been agreed that, from January 2015, the pilot will be extended to applications for generic medicinal products through the Centralised Procedure. In the initial phase, 10 applications for generic products will be selected for participation to the pilot; further products might be considered after evaluation of the results of the initial phase. An outline of the process and information on how to express interest for participation to the pilot are published on the Related Documents section of this website. By allowing to share assessment reports with non-EU regulatory agencies like the TGA, will assist collaboration and information-sharing between regulatory authorities across the world, contributing to facilitating and strengthening the scientific assessment process for medicines. This should enable medicines to be authorised in different territories in a coordinated way at approximately the same time. The first phase of the pilot project will involve the EU, Australia, Canada, Chinese Taipei and Switzerland. Other members of the IGDRP may decide to take part in the pilot programme at a later stage. These include Brazil, China, Japan, Korea, Mexico, New Zealand, Russia, Singapore and South Africa. The European Directorate for the Quality of Medicines & Healthcare (EDQM) and the World Health Organization (WHO) participate in IGDRP meetings as observers. This is one of the work programs under the IGDRP. Other areas of cooperation in which the TGA is involved include work sharing possibilities in the area of active substance master file, inspection of sites conducting bioequivalence and bio-analytical studies and information sharing on pharmaceutical quality issues. The TGA is encouraging eligible generic medicines manufacturers to consider taking part in this exciting and ground breaking pilot programme. Further information about how to participate in the pilot programme can be found below by downloading the EOI documentation package.
  15. 15. PHARMA UPTODAY 15 Responses to this EOI are requested by 31 March 2015 The below EOI provides information package for the pilot including: 1. List of eligibility criteria. 2. EOI request form to participate in the pilot. The form includes a section seeking consent from sponsors for the EU DCP to share assessment reports with pilot participants and other IGDRP member agencies of the sponsor's choosing in real time. 3. Contact information at participating regulatory agencies. 4. Summary of Quality Differences form. Please forward the enclosed EOI to the contact points for each selected agency in your EOI. The contact for the TGA is: PCSinbox@tga.gov.au(link sends e-mail) New vice-chair appointed to Commission on Human Medicines Dr Angela Thomas has been appointed as vice-chair of the Commission on Human Medicines (CHM). She replaces Professor Ian Weller who retired from the position and from CHM on 31 December 2014. The CHM advises on matters relating to safety, quality and the efficacy of medicines as well as the collection of adverse drug reactions. Dr Angela Thomas is a consultant paediatric haematologist at the Royal Hospital for Sick Children in Edinburgh, a fellow of the Royal College of Physicians in Edinburgh, a former President of the British Society for Haematology and has been on the CHM since 2005, where she chairs the Clinical Trials, Biologicals & Vaccines Expert Advisory Group. She has also served as a member and chaired many scientific and medical committees in the UK and Europe. Dr Angela Thomas said: ―I am delighted to be taking up this new role. The Commission plays a vital role in the licensing of new medicines and in monitoring drug safety. ―I have found my time as a member of CHM tremendously rewarding and am looking forward to the challenges offered in my new role as vice-chair.‖
  16. 16. PHARMA UPTODAY 16 FDA’s investigation into patients being injected with simulated IV fluids continues FDA and the Centers for Disease Control and Prevention (CDC) are continuing to investigate multiple instances of Wallcur‘s simulated intravenous (IV) saline products being administered to patients. These products are not sterile and should not be injected in humans or animals. Wallcur‘s simulated IV saline solution, Practi-0.9% sodium chloride solution, was shipped to medical clinics, surgical centers, and urgent care facilities in numerous states. So far, more than 40 patients have received infusions of the simulated saline products, and there have been many adverse events associated with these incidents including fever, chills, tremors and headache. Some patients were hospitalized, and there is one death associated with the use of these products; it is not known if this death is directly related to the use of the product. Adverse events have been reported in seven states: Florida, Georgia, Idaho, Louisiana, North Carolina, New York, and Colorado. FDA, in partnership with CDC, has collected samples of Wallcur Practi 0.9% Sodium Chloride from clinics and distributors. These products are being tested to learn if the products may have caused the adverse events in patients. Wallcur initiated a voluntary recall of Practi-0.9% sodium chloride IV solutions. Most medical facilities reported that they were unaware that the IV solution bags were simulation products. At least one clinic recognized the Wallcur product was a simulation product upon receipt, and returned it to the distributor. FDA is working with distributors who sold the simulated IV products and clinics that purchased and administered the simulated IV products from Wallcur to determine how these simulation IV solution products entered the supply chain and subsequently were administered to patients. While Sodium Chloride 0.9% Injection (IV normal saline) has been in tight supply, FDA has been working with manufacturers to increase supply. In addition, FDA is not objecting to the temporary distribution of additional IV normal saline from alternate sources Fresenius Kabi USA, Baxter Healthcare Corp., and B. Braun Medical Inc.Currently, there is supply available from several manufacturers as posted on FDA‘s website. Healthcare Providers Clinicians and office staff are encouraged to take steps to ensure IV solution simulation products are removed from office inventory to eliminate the possible injection of Wallcur simulated products into patients.
  17. 17. PHARMA UPTODAY 17  Visually inspect all current IV saline solution bags. Ensure none of the bags are labeled ―Wallcur,‖ ―Practi-products,‖ ―For clinical simulation,‖ or ―Not for use in human or animal patients.‖  If you have products labeled with any of these words, or you suspect you may have received other products intended for training purposes, separate simulation products from existing inventory and contact your distributor for directions on how to return these products.  If you have received Wallcur Practi-products by mistake, please contact the distributor, or Wallcur, LLC of San Diego for return instructions.  Consider reviewing your office procedures and make sure there are procedures in place to visually inspect all future shipments of normal saline products to ensure they are for clinical use. If you suspect that any Wallcur training IV products may have been administered to a patient, whether or not the incident has resulted in an adverse event:  Evaluate all potentially exposed patients with new, or ongoing symptoms;  Use appropriate treatment;  Report suspected cases to the state health department; and  Report any adverse events following use of these products to FDA‘s MedWatch program online or at 1-800-332-1088. Patients  Patients who believe they received an injection of Wallcur simulated IV solution should contact their health care provider.  Patients who received simulated IV saline almost immediately upon injection experienced fever, chills, muscle aches, headaches, and some required hospitalization. In most reported cases, these signs and symptoms were immediately recognized and patients received appropriate medical attention.  You may also file a report of the incident through FDA‘s MedWatch program, and assist the FDA with this ongoing investigation.  If you know you will be receiving normal saline, ask your doctor or nurse to visually inspect the bag, and ensure they are using normal saline for human use. Ensure the bag is not labeled or printed with any of the following: ―Wallcur,‖ ―Practi-products,‖ ―For clinical simulation‖ or ―Not for use in human or animal patients.‖ If the saline bag contains any of these words, ask your health care provider NOT to administer the solution. Wholesalers, Distributors, Suppliers
  18. 18. PHARMA UPTODAY 18  Inspect your inventory and ensure you are not distributing simulated products as clinical use products.  It is incumbent upon wholesalers, distributors, and suppliers to clearly and accurately label and distribute their products to prevent medical product mix-ups from occurring.  If you suspect you may have distributed this product to clients by mistake, immediately attempt to recall the products and warn clients of the potential risks. You should also contact Wallcur, your distributor and file a report to FDA‘s MedWatch program. FDA warns health care professionals not to inject patients with IV solutions from Wallcur, of San Diego [12/30/14] The U.S. Food and Drug Administration is alerting health care professionals not to use Wallcur, LLC, simulated intravenous (IV) products in human or animal patients. These products are for training purposes only. Before administering IV solutions to patients, health care providers should carefully check the labels to ensure that the products are not training products, such as Practi IV Solution Bags marketed by Wallcur. Wallcur‘s training products, which may bear the words ―for clinical simulation,‖ are not to be administered to patients. FDA has become aware that some Wallcur training IV products have been distributed to health care facilities and administered to patients. There have been reports of serious adverse events associated with the use of certain of these products – i.e., Practi IV Solution Bags. If you suspect that any Wallcur training IV products may have been administered to a patient, whether or not the incident has resulted in an adverse event, please report the incident to FDA‘sMedWatch Adverse Event Reporting program by:  Completing and submitting the report online at MedWatch Online Voluntary Reporting Form  Downloading and completing the form (PDF - 1.22MB), then submitting it via fax at 1-800- FDA-0178
  19. 19. PHARMA UPTODAY 19 FDA will continue to investigate and monitor this issue. The agency is also working with the Centers for Disease Control and Prevention to inform health care professionals and state health departments. Product Tracing in the USA With the Drug Supply Chain Security Act (DSCSA) and the related implementation plan over a ten year period dated from 2013 new requirements were defined in the USA which are to improve the traceability of prescription drugs within the supply chain. With the inclusion in the Federal Food, Drug and Cosmetic Act under Section 582 the FDA is authorised to implement a system in the USA which is to guarantee the traceability of drugs in the USA. This concerns manufacturers, wholesale distributors, and repackagers of certain prescription drugs. According to the time plan the requirements for generating, providing and archiving (6 years) of product-tracing information (transaction information (TI), transaction history (TH) and transaction statements (TS)) were scheduled to go into effect on January 1, 2015. An FDA Guideline that was released already in December 2014 has postponed the start. From a mere technical point of view January 1, 2015 remains the date of entry into force. However, the FDA states that it does not intend to take action against companies who do not comply with the DSCSA prior to May 1, 2015. This equals a postponement of four months. The reason for this deferment might be the fear that there could be drug shortages in the USA because of the companies not being able to comply with the new requirements. But the date for the next step, the start for the introduction of serialisation still remains 2017. Frequent Findings in Supplier Qualification Supplier Qualification is a hot topic in inspections. The inspectorates' summaries of their observations show that things do not always work as desired. In a presentation published by the end of last year by the U.K. authority MHRA (Medicines and Healthcare Products Regulatory Agency), it is stated that "deficiencies relating to 'Quality Systems' are by far the most prevalent observed during inspections". The report "GMP Inspection Deficiencies 2013"
  20. 20. PHARMA UPTODAY 20 covers 630 inspections performed in 2013. According to the report, deficiencies in supplier and contractor audits are amongst the top 5. Taking a closer view at the examples of the observations, one can see that problems arise and the whole area of supplier qualification like auditing, audit plan, audit report, adequate contracts and managing unapproved suppliers:  The respective audit report was not available.  There was no evidence upon which to base the approved manufacturer decision  The address of a supplier site differed from the address on the audit report  In the audit reports it was not apparent what had actually been audited  The maintenance and control of the approved supplier list was not robust  API was received although an audit specified that the supplier was no longer approved  Risk based audit planning defines no maximum time frequency  Quality Assurance Agreement was not kept up to date.  Quality Assurance Agreement failed to adequately describe transportation conditions.  Approved supplier list was inadequate, e.g. not all suppliers were listed and some suppliers were listed that should not have been.  Supplier audit SOP did not cover API suppliers and other services.  After concluding that an API supplier was not suitable for the supply, the API already received and held on stock was not quarantined and rejected. CHMP adopts ICH Q3D Guideline as "Scientific Guideline" After the publication of a final ICH guideline, its implementation into the respective national regulations of the 3 ICH regions Europe, USA and Japan (Step 5 of the ICH process) is usually the next step. The "ICH Guideline for elemental impurities - Q3D" was published on 19 December 2014 as Step 4 document. Four weeks later - on 12 January 2015 - the integration of the Guideline into EMA's set of rules of "Scientific Guidelines" was notified after the CHMP committee had adopted it through a formal act. As for all the ICH guidelines which are integrated into the collection of "Scientific Guidelines",
  21. 21. PHARMA UPTODAY 21 the corresponding EMA Guideline which is now entitled "ICH guideline Q3D on elemental impurities" is composed of only one table of the document history and the section "scope" identical to that of the original ICH guideline. After that, there is just a direct link to the ICH page containing the "Quality Guidelines" where the Q3D can be easily found. The table with the document history contains important information for the pharmaceutical and API industry of the EU member states about the coming into force of the ICH Q3D requirements. These regulations will be binding:  As of June 2016 for new marketing authorisation applications and  As of December 2017 for authorised medicinal products The time window for the verification of authorised and/ or already marketed medicinal products for compliance with the limits regarding elemental impurities/ acceptable daily doses is now only 3 years. FDA's new Quality Metrics Program to plan GMP Inspections The US Food and Drug Administration has initiated a comprehensive new organisation of its inspection activities. One of the key elements of this initiative is the Quality Metrics Program. This program will throw a complete new light on the compliance status of each manufacturing site. So far there were only two categories: GMP compliance or non-compliance. There was no benefit for industry to improve the overall quality as long as the manufacturing site was rated to be in GMP compliance. Chances have been good that a non compliance situation was not discovered by FDA inspectors. The frequency of inspections - especially those in foreign countries - was not meeting internal FDA standards. Instead of inspecting at least every two years, some facilities have not been inspected for a long period of time. As a result some major GMP deviations have been discovered at manufacturing sites and have caused comprehensive compliance actions such as FDA Warning Letters and Import Alerts. This has resulted in some serious drug shortages because medicinal products were only manufactured at very few manufacturing sites.
  22. 22. PHARMA UPTODAY 22 The FDA Quality Metrics initiative aims at asking each production site (APIs, medicinal products, Biotech, OTC etc) to provide data about the "quality level" in the manufacturing site. By this, FDA will be able to see from the data how well the quality system is maintained and how successful the quality system will affect the quality of the medicinal products. At the 17th APIC Conference on APIs FDAs Russel Wesdyk presented details on how FDA will collect data from the companies. The Food and Drug Administration Safety and Innovation Act (FDASIA) Title VII, section 706 gives US FDA the authority to collect Quality Metrics. Over the last year a number of meetings have been organised in order to discuss potential Quality Metrics with stakeholders. As an outcome of these meetings the following Quality Metrics are of high interest for FDA: Lot Acceptance Rate = the number of lots rejected by the establishment in a year divided by the number of lots attempted by the same establishment in the same year. Right First Time Rate = the number of lots with at least one deviation by the establishment in a year divided by the number of lots attempted by the same establishment in the same year. Product Quality Complaint Rate – the number of complaints received by the manufacturer of the product concerning any actual or potential failure of a unit of drug product to meet any of its specifications, divided by the total number of lots released by the manufacturer of the product in the same year. Invalidated Out-of-Specification (OOS) Rate – the number of OOS test results invalidated by the establishment, or contracted establishment in a year divided by the total number of tests performed by the establishment in the same year. Annual Product Review (APR) on Time Rate – the number of APRS generated within 30 days of annual due date at the establishment divided by the number of products produced at the establishment Management Engagement – the most senior manager that signed each annual product review, reported as one of the following: (1) none specified, (2) line quality manager, (3) site operations manager, or (4) corporate executive manager. - Performance Question 1 – A ―yes‖ or ―no‖ value of whether the establishment calculated a process capability or performance index for each critical quality attribute as part of that
  23. 23. PHARMA UPTODAY 23 product‘s APR. - Performance Question 2 - A ―yes‖ or ―no‖ value of whether the establishment has policy requiring a CAPA at some lower process capability or performance index. - Performance Question 3 – If ―yes‖ to question 2 – what is the process capability or performance index that triggers a CAPA. If ―no‖ to question 2 – please do not respond. Corrective and Preventative Action (CAPA) Rate – the number of corrective or preventative actions that were initiated due to an APR, divided by the total number of APRs generated. The FDA will use the Quality Metrics in a learning period of approx. one year. After that learning period serious compliance actions will be the consequence for not reporting to FDA. The next steps will happen very soon. The FDA is planning to publish the Draft Guide on Quality Metrics in the next months to come. International harmonisation of ingredient names The TGA is working on the complex and important task of updating Australian ingredient names to align with international naming systems, such as the World Health Organization's International Non-proprietary Name (INN) system. As part of this activity, we are also looking at changes to improve the consistency of ingredient names used in Australia. In May 2013, TGA and the New Zealand regulator, Medsafe, sought comments from interested parties on proposed changes to approximately 472 ingredient names, and an update to the guidance document TGA approved terminology for medicines. Thirty-one submissions were received - 28 were submitted to TGA and 3 were submitted to Medsafe. Responses were received from the pharmaceutical industry, as well as healthcare professional and consumer organisations. TGA also held focus groups with some stakeholders to discuss the proposed name changes and seek feedback on implementation strategies. For more details browse: https://www.tga.gov.au/submissions-received-international- harmonisation-ingredient-names Karnataka DC insists on adherence to Para 15 C of Sch L1 in D&C Rule for data integrity compliance Karnataka drugs controller has stated that root cause of non-compliance issues are often linked to human errors. It is also attributed to the lackadaisical attitude of the pharma industry personnel which also include senior management officials. Non-compliance to data integrity has resulted in global regulatory inspection failures for some
  24. 24. PHARMA UPTODAY 24 Indian companies. Therefore every effort should be made by the industry to ensure adherence and should closely look at Para 15 C of Schedule L1 of Drugs and Cosmetics Rule 1945 which also mandates the requirements about data integrity and security, said Raghurama Bhandary, drugs controller, government of Karnataka. ―Data integrity calls for trust of information and records. Data should be reliable, complete and accurate. Moreover, data should be authentic and proven to be what is mentioned. This data should be usable, easily located, retrieved, presented and interpreted, he said at a recently concluded day lone International Society for Pharmaceutical Engineering (ISPE) seminar. As per the US FDA, data integrity will focus on back backdated, postdated and missing signatures. It will also help detect fabricates or fake data, besides copying existing data as new data. Further, it will also indicate re-running samples, discarding data or omitting negative data, releasing failure product, testing information until the product is released. It will also detect hiding or obscured standard operating procedures or protocol deviations. In addition, it will indicate not saving data electronically or even as hard copies, poor documentation control, inappropriate audit trials, inadequate access authorisation, inadequate reporting of failure and deviation management, data back up and disaster recovery, use of an invalidated software application, mismatch between reported data and actual data, he said. India has over 300 US FDA approved manufacturing facilities which manufacture generics. The Indian pharma industry turnover of Rs. 1.38 lakh crore of which Rs. 90,000 crore is exports. ―Data integrity issue is prevalent globally and not merely India centric. If the pharma industry in the country is engaged in the production of life-saving drugs then it cannot afford to be negligent. We need to be careful and it is absolutely fair by global regulators to keep tabs on this. Therefore it is not that India pharmaceutical companies are targeted by the global regulators,‖ stated the Karnataka drugs controller. Since the ISPE event also focused on need quality culture, corrective and preventive action (CAPA) , and investigation, the Karnataka drugs controller said that adherence to robust quality systems would lead to data integrity, CAPA improvements will bring in systematic processes. GVK Biosciences: European Medicines Agency recommends suspending medicines over flawed studies Medicines considered critically important for patients to remain available A number of medicines for which authorisation in the European Union (EU) was primarily based on clinical studies conducted at GVK Biosciences in Hyderabad, India should be suspended,
  25. 25. PHARMA UPTODAY 25 says the European Medicines Agency (EMA). The recommendation is based on findings from an inspection that raised concerns about how GVK conducted studies at the Hyderabad site on behalf of marketing authorisation holders. Upon the request of the European Commission, EMA‘s Committee for Medicinal Products for Human Use (CHMP) looked at over 1,000 pharmaceutical forms and strengths of medicines studied at the GVK site. For over 300 of them, sufficient supporting data from other sources were available; these will therefore remain on the market in the EU as EMA is satisfied with the available data. For medicines that lack data from other studies, the CHMP recommended suspension unless they are of critical importance for patients because alternatives will not be able to meet patients‘ needs. There is no evidence of harm or lack of effectiveness linked to the conduct of studies by GVK Biosciences. The decision on whether a medicine is critical for patients lies with the national authorities of EU Member States depending on the situation in their country. For medicines that are considered critical, companies are given 12 months to submit additional data. The full list of medicines for which the CHMP recommends suspension is available on the EMA website. The inspection of GVK that led to the CHMP‘s recommendation was carried out by the French medicines agency (ANSM). The inspection revealed data manipulations of electrocardiograms (ECGs) during the conduct of some studies of generic medicines. These manipulations appeared to have taken place over a period of at least five years. Their systematic nature, the extended period of time during which they took place and the number of members of staff involved cast doubt on the integrity of the way trials were performed at the site generally and on the reliability of data generated at that site. EMA and national authorities work closely with international partners to ensure that studies underpinning marketing authorisations in the EU are carried out to the highest standards and that the companies involved comply fully with all aspects of Good Clinical Practice (GCP). The CHMP‘s recommendation will be sent to the European Commission for a legally binding decision. This decision will apply to all Member States irrespective of whether or not they have taken interim measures to suspend medicines. Information to patients and healthcare professionals
  26. 26. PHARMA UPTODAY 26 A number of medicines are being considered for suspension in EU countries following concerns about how studies may have been conducted at GVK Biosciences‘ site in Hyderabad, India. Patients and healthcare professionals are advised of the following:  There is no evidence of harm or lack of effectiveness with any of the medicines linked to studies conducted by GVK.  Some medicines, for which insufficient alternatives are available to meet patients‘ needs, will remain on the market in some countries as new data are being awaited.  National authorities in the EU will consider the availability of individual medicines in their countries and make final decisions on whether to suspend or allow continued availability, while new data are awaited.  Patients should continue to take their medicines as prescribed. Source: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2015/01/WC5 00180902.pdf Change Control: New FDA Expectations for Equipment Changes The U.S. Food and Drug Administration (FDA) has published a new Manufacturing Equipment Addendum for the SUPAC Guidelines (Scale-up and post-approval changes), describing the administration's expectations when assessing manufacturing equipment changes. This Guidance for Industry combines and supersedes the following Guidances:  SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms, Manufacturing Equipment Addendum  SUPAC-SS: Nonsterile Semisolid Dosage Forms, Manufacturing Equipment Addendum The biggest alteration was the removal of the lists of specific manufacturing equipment that were in both guidances. It now contains general information on SUPAC equipment. The reason is that FDA was concerned that misinterpretation of the lists could discourage advancements in manufacturing technologies. Furthermore, it clarifies the types of processes being referenced. The information in the document is presented in broad categories of unit operation. For each operation, equipment is
  27. 27. PHARMA UPTODAY 27 categorized by class (operating principle) and subclass (design characteristic). Examples of types of equipment, but not specific brand information, are now given within the subclasses. When assessing manufacturing equipment changes; FDA recommends to follow "a risk-based approach that includes a rationale and complies with the regulations, including the cGMP regulations". They also recommend "addressing the impact on the product quality attributes of equipment variations (via process parameters) when designing and developing the manufacturing process". Leakages in Ampoules cause Recalls Again, there is a recall of sterile ampoules in Switzerland. The manufacturer stated a possible leakage as reason for the recall. The area concerned seems to be the breaking point as was the case in the recall by Streuli Pharma in 2013. This case was presented at the ECA Conference "Particles in Parenterals and beyond" in Copenhagen in September 2014. Product had crystallized on the outer surface of the ampoule at the breaking point. Although the leakage could not be verified with any method available and no contamination of the product came to be known it was not possible to exclude that microorganisms could penetrate into the ampoule. Consequently, non-sterility could not be excluded. According to a statement from Streuli Pharma this packaging material problem could not be solved so that they had to change the primary packaging material within a very short time. You can find the case which occurred only now but is described in an analogous way at the page of Swissmedic. Another sterile medicinal product had to be recalled in Switzerland because of crystallization of the product (particle formation) in the solution for injection. Batches of another product were withdrawn from the market because of possible metal particles already in October. Novartis expects 10 NME filings by end 2016 Novartis told investors today that it is entering a particularly fruitful period of product development, with 10 new molecular entities (NMEs) due to be submitted for approval in 2015 and 2016. The hike in R&D output for the company's pharmaceuticals division comes after a transitional
  28. 28. PHARMA UPTODAY 28 year for the company which saw it divest animal health and vaccines operations and set up a joint venture for over-the-counter drugs, allowing it to focus on its prescription medicine and eyecare businesses. The new crop of filings - which includes potential blockbusters for cancer and heart failure - is coming through while Novartis is still enjoying buoyant growth for recently launched products, including oral multiple sclerosis therapy Gilenya (fingolimod), Jakavi (ruxolitinib) for myelofibrosis and its stable of therapies for chronic obstructive pulmonary disease (COPD). Moreover, the company has just scored approvals in the US, EU and Japan for Cosentyx(secukinumab), a first-in-class interleukin-17 inhibitor with blockbuster potential in psoriasis and related disorders, and has also filed LCZ696, a much-anticipated new drug for chronic heart failure that at least one analyst has suggested could be an $8 billion product. This year should see regulatory filings for buparlisib (BKM120), a P13K inhibitor for breast cancer, LCQ908 for the rare disease familial chylomicronemia syndrome (FCS) and acute myeloid leukaemia candidate midostaurin (PKC412), an orally-active FLT3 inhibitor. During 2016 Novartis is expecting no fewer than seven marketing applications, including RLX030 for acute heart failure and - arguably most notably - CAR T cell therapy CTL019 for acute lymphoblastic leukaemia (ALL). Novartis chief executive Joe Jimenez told investors today that the new product cycle is setting up the company for strong revenue growth in the coming years. "We delivered solid sales growth with margin expansion, strengthened innovation, and advanced our quality and productivity agendas," he said. His comments came as Novartis reported declines in both revenues and profits in the fourth quarter of 2014 on the back of generic competition, restructuring costs and currency factors. The company earned net profit of $1.49 billion - down almost 27 per cent - on revenues that fell 2 per cent to $14.63 billion. Turnover of Novartis' biggest selling drug Glivec/Gleevec (imatinib) for chronic myeloid leukaemia and gastrointestinal stromal tumours (GIST) was largely flat at $1.24 billion in the quarter, while follow-up Tasigna (nilotinib) climbed 30 per cent to $428 million. Among Novartis' other new products, Gilenya rose 32 per cent to $666 million, kidney cancer drug Afinitor (everolimus) brought in $426 million - a rise of 24 per cent - and Jakavi leaped by more than 70 per cent to $84 million.
  29. 29. PHARMA UPTODAY 29 Novartis' COPD franchise - including recently-introduced combination product Ultibro(indacaterol/glycopyrronium) - also put in a strong showing with full-year sales almost doubling to reach $484 million. In 2015, Novartis is forecasting mid-single digit sales growth and a high-single digit rise for core operating income. INDIAN PATENT OFFICE REJECTS ALMOST HALF OF ALL PHARMA PATENTS As we finish the first month of 2015, the Office of India‘s Controller General of Patents, Designs and Trademarks (CGPDT) has issued a number of adverse patent decisions that directly impact the U.S. life sciences industry. A publicly notable example is the January 14, 2015 rejection by CGPDT of a patent application from Gilead that includes claims covering its breakthrough hepatitis C drug, Sovaldi® (sofosbuvir) (Gilead Solvadi Decision). In our January 16 ―Insight on India‖, we discussed this decision in particular, especially as it relates to CGDPT interpreting the highly controversial Section 3(d) of the India Patents Act, 1970 to refuse to grant Gilead‘s patent application 4249/KOLNP/2007. According to press reports, Gilead has indicated that it will appeal the decision. In reviewing a sample size of patent application decisions by CGDPT to date in 2015, Section 3(d) of India‘s Patent Act remains a frequently used basis to examine patent applications. Section 3(d) states: (d) the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant. Explanation.—For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy; This provision has led to denial of several patent applications, which according to Western pharmaceutical and biotechnology companies (hereinafter collectively referred to as ―biopharmaceuticals‖) has limited their ability to market their products in the Indian market. Other stakeholders such as generic pharmaceutical manufacturers and non-government
  30. 30. PHARMA UPTODAY 30 organizations (NGOs) have supported the Indian Government‘s narrow interpretation of provisions such as section 3(d) in limiting patentability on the grounds that it would prevent so- called ―evergreening‖. As usual, the truth can be found somewhere in between. In reviewing CGDPT patent application decisions between January 12-23, 2015, 43 patent relevant applications were identified as covering the biopharmaceuticals or medical devices sectors), 34 covered pharmaceuticals (79 percent), six for medical devices (14 percent), and three for biotechnology (7 percent). Note that we did not look at non-human health biotechnology patent applications. All patent decisions are listed in Appendix A. Of the CGDPT decisions regarding the above-referenced 43 patent applications, 17 applications (40 percent) listed the United States as the country of origin of the applicant. Nineteen (44 percent) were from Western Europe or other developed countries. Only six (14 percent) were from Indian companies, e.g., Lupin, Wockhardt, or Indian government research agencies such as the Council of Scientific and Industrial Research (CSIR). Interestingly, of those six from India, all four from Indian pharmaceutical companies were applications for process patents that did not claim a new chemical entity. Of the 43 patent decisions by CGDPT, 24 patent applications proceeded to grant while 19 patent applications were refused to proceed to grant. Of the 34 pharmaceutical patent applications, 18 proceeded to grant (53 percent) and 16 refused (47 percent). Of the six medical device patent applications, two were refused (33 percent) and four were given the green light to proceed to grant (67 percent). Finally, one of three biotech patent applications was refused and two were permitted to proceed to grant. During the two-week period under study, of the 34 pharmaceutical patent applications, 53 percent were allowed to proceed to grant and 47 percent were refused. Looking more closely at the 16 pharmaceutical patent applications that were refused, eight of 16 (50 percent) were due to the applicant no longer being interested in pursuing the application,
  31. 31. PHARMA UPTODAY 31 thus leading to their refusal. Ten of the 16 pharmaceutical refused patent applications (63 percent) had objections from the patent examiner relating to lack of invention or novelty, obviousness, or a failure to meet criteria set out in Sections 3 or 15 of the Indian Patent Act, including both Section 3(d) and 3(e). Two other divisional patent applications did not demonstrate sufficient distinction from the parent application and therefore were refused to proceed to grant. Finally, of the 19 patent applications that had been refused, three of the applicants had patents already granted to them for the same invention in other jurisdictions, e.g. United States, Japan or Europe. All three of these patent applications included claims for pharmaceuticals. The rest had patent applications still pending in other locations, including Gilead. While this sample size is too small to draw any larger conclusions from this analysis, it is fair to say that the value of IPR and the decisions made by CGDPT is something that will be closely watched and scrutinized by U.S. life sciences companies. Panel on amendments in D&C Rule forms 7 sub-groups on drugs, medical devices, clinical trials, biologicals, etc The Union Health Ministry's high level committee, constituted for examining and recommending amendments in the Drugs and Cosmetics Rules, 1945, has set up seven sub-groups for different segments like drugs, medical devices, clinical trials, biologicals, blood banks and cosmetics with a nodal person from the industry and a resource person from the CDSCO. Vikas Kumar of ISCR will be the nodal coordinator for the sub-group on Clinical Trials (Drugs), while Dr. A.K Pradhan, DDC(I), will be the CDSCO resource person of this sub-group. Sumati Randeo of CII will be the nodal coordinator for the sub-group on Clinical Trials (Medical Devices & IVD), while Dr. Eswara Reddy, JDC(I), will be the CDSCO resource person of this sub-group. The sub-group on Pharmaceuticals has three nodal coordinators from the industry--Arun Mishra (CII), Ashok Madan (IDMA) and Meenu Batolar (OPPI). Dr. V.G. Somani, JDC(I), has been made the resource person of this sub-group from the CDSCO. Rakesh Sharma of FICCI will be the nodal coordinator for the sub-group on Medical Devices & IVD, while Dr. Eswara Reddy, JDC(I), will be the CDSCO resource person of this sub-group. Shobha Mishra Ghosh of FICCI will be the nodal coordinator for the sub-group on Biological &
  32. 32. PHARMA UPTODAY 32 OTC, while Dr. V.G. Somani, JDC(I), will be the CDSCO resource person of this sub-group. Likewise, Elzabath Jose of CII will be the nodal coordinator for the sub-group on Blood Bank, while Dr. V.G. Somani, JDC(I), will be the CDSCO resource person of this sub-group. Sumeet Jaiswal of IBHA will be the nodal coordinator for the sub-group on Cosmetics, while Dr. Sudipta, DDC (I), will be the CDSCO resource person of this sub-group. Dr. B. R. Jagashetty, National Advisor (Drugs) will be the overall coordinator for all sub-groups. The first meeting of this high powered committee, under the chairmanship of Joint Secretary (Regulation), Department of Health and Family Welfare, was held on January 21, 2015. Besides the committee members, the meeting was attended by representatives of industry associations. It was agreed in the meeting that 31st January, 2015 would be the last date for sending comments on the proposed amendments in the said Rules. Earlier in December 2014, the union health ministry decided to constitute this high level committee to expeditiously revisit the Drugs and Cosmetics Rules, 1945 and make recommendations for amending the same in order to make these rules contemporary while keeping in view the requirements of quality, safety and efficacy of medical products and also the efficiency of regulatory structures and the industry and to keep pace with changing scenario of drugs, medical devices and cosmetics industry. The other members of the committee are Dr B R Jagashetty, National Advisor (Drugs Control) and Project In-charge; S R Dhaleta, Retired Joint Secretary & Legislative Counsel, Legislative Department, Ministry of Law & Justice; a representative of the Department of Legal Affairs, Ministry of Law & Justice;a representative of Department of Pharmaceuticals; Dr V G Somani, Joint Drugs Controller (ad-hoc), Central Drugs Standard Control Organization; D K Shringi, Retired Drug Controller, Rajasthan; G L Singhal, Retired Drug Controller, Haryana; Dr G Selvaraj, Retired Deputy Drug Controller, Tamil Nadu; and representatives of all Industry Associations. Actavis to buy Auden Mckenzie for GBP306m Actavis, a leading global specialty pharmaceutical company, and the owners of Auden Mckenzie Holdings Limited, a dynamic and fast growing company focused on the development, licensing and marketing of niche generic medicines and proprietary brands in the UK, announced that they have reached a definitive agreement, under which Actavis will acquire Auden Mckenzie for approximately £306m in cash, plus a two-year royalty on a percentage of gross profits of one of Auden Mckenzie's products.
  33. 33. PHARMA UPTODAY 33 Auden Mckenzie will be acquired on a debt free basis, and the transaction will exclude Auden Mckenzie's real estate portfolio. The acquisition will make Actavis the number one supplier of generic pharmaceuticals in the UK. Following the close of the acquisition, and the anticipated combination of Actavis and Allergan later this year, Actavis will hold the number three position in the supply of UK pharmaceuticals. The acquisition of Auden Mckenzie is expected to be immediately accretive to Actavis' non-GAAP earnings in 2015. Actavis currently markets more than 650 generic products in the UK, and has approximately 85 additional products under registration and development. The combination with Auden Mckenzie is anticipated to add approximately 175 new generic and branded products, as well as a pipeline of approximately 40 additional products, in various dosage forms, for treatments across a broad spectrum of therapeutic areas. The acquisition is subject to certain conditions, including approval by regulatory authorities, and is expected to close in the first quarter of 2015. "Auden Mckenzie is one of the leading pharmaceutical companies in the UK, and the opportunity to combine this profitable and growing company into the Actavis UK business demonstrates our commitment to invest in and expand strategically in our global generics business," said Brent Saunders, CEO and President of Actavis. "This strategic combination is highly synergistic with our UK business, is immediately and highly accretive and reflects our commitment to invest to achieve a top position in key international markets," added Robert Stewart, Actavis Chief Operating Officer and incoming Executive Vice President Actavis, and President, Generics and Global Operations. "Since its inception in 2000, Auden Mckenzie has established a notable position among the UK niche generic businesses by adopting a dynamic and entrepreneurial approach to developing and marketing generic medicines," said Amit Patel, Managing Director of Auden Mckenzie. "We see in Actavis a company with the same entrepreneurial qualities. With its multinational resources and scope, Actavis will be able to achieve further growth based on Auden Mckenzie's existing products and pipeline of new products."
  34. 34. PHARMA UPTODAY 34 Data: Information derived or obtained from raw data (e.g. a reported analytical result) Data must be: A - attributable to the person generating the data L – legible and permanent C – contemporaneous O – original (or ‗true copy‘) A - accurate Raw data: Original records and documentation, retained in the format in which they were originally generated (i.e. paper or electronic), or as a ‗true copy’. Raw data must be contemporaneously and accurately recorded by permanent means. In the case of basic electronic equipment which does not store electronic data, or provides only a printed data output (e.g. balance or pH meter), the printout constitutes the raw data. Original records Raw data must: • Be legible and accessible throughout the data lifecycle. • Permit the full reconstruction of the activities resulting in the generation of the data Metadata: Metadata is data that describe the attributes of other data, and provide context and meaning. Typically, these are data that describe the structure, data elements, inter- relationships and other characteristics of data. It also permits data to be attributable to an individual. Metadata forms an integral part of the original record. Without metadata, the data has no meaning. Data Integrity : The extent to which all data are complete, consistent and accurate throughout the data lifecycle.
  35. 35. PHARMA UPTODAY 35 New Guidance FDA Releases Manual of Policies and Procedures (MAPP) 4100.1 CDER Co-Sponsorship Agreements for Events The purpose of this MAPP is to ensure consistency and continuity across CDER as the Center engages in not-for-profit events (e.g., conferences, meetings, symposia, webinars, and workshops) co-sponsored with outside non-Federal organizations that provide relevant expertise and share a mutual interest and benefit in the subject matter. Pursuant to this MAPP, a network of CDER Co-Sponsorship Coordinators will be established to manage CDER co- sponsorships with outside organizations. Guidance for Industry: DSCSA Implementation: Product Tracing Requirements — Compliance Policy This guidance is intended for trading partners (manufacturers, wholesale distributors, and repackagers) who must provide and capture certain product tracing information, as required under section 582 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360eee- 1). This guidance addresses the readiness of the pharmaceutical distribution supply chain to comply with the provisions in section 582 of the FD&C Act related to the exchange of product tracing information. Requirements for the tracing of products through the pharmaceutical distribution supply chain go into effect on January 1, 2015, for manufacturers, wholesale distributors, and repackagers, and on July 1, 2015, for dispensers. Recently posted US FDA guidance documents These draft and final guidance documents were published by the Food and Drug Administration in December 2014: 12/1/14: SUPAC: Manufacturing Equipment Addendum 12/2/14: Infusion Pumps Total Product Life Cycle - Guidance for Industry and FDA Staff 12/2/14: Recommendations for Labeling Medical Products to Inform Users that the Product or Product Container is not Made with Natural Rubber Latex - Guidance for Industry and Food and Drug Administration Staff 12/3/14: Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products-Content and Format 12/4/14: How to Obtain a Letter from FDA Stating that Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable REMS for RLD 12/8/14: General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products 12/8/14: DSCSA Implementation: Annual Reporting by Prescription Drug Wholesale Distributors and Third-Party Logistics Providers
  36. 36. PHARMA UPTODAY 36 12/9/14: Patient Counseling Information Section of Labeling for Human Prescription Drug and Biological Products — Content and Format 12/10/14: VICH GL35 - Pharmacovigilance of Veterinary Medicinal Products Electronic Standards for Transfer of Data 12/11/14: Establishing Safety and Compatibility of Passive Implants in the Magnetic Resonance (MR) Environment - Guidance for Industry and Food and Drug Administration Staff 12/17/14: Providing Submissions in Electronic Format -- Standardized Study Data 12/19/14: Minimizing Risk for Children's Toy Laser Products - Guidance for Industry and Food and Drug Administration Staff 12/22/14: Transfer of a Premarket Notification (510(k)) Clearance – Questions and Answers Draft Guidance for Industry and Food and Drug Administration Staff 12/23/14: DSCSA Implementation: Product Tracing Requirements — Compliance Policy 12/30/14: Radiation Biodosimetry Devices - Draft Guidance for Industry and Food and Drug Administration Staff MHRA New essential Orange and Green Guides 2015 – out now! The latest UK pharmaceutical regulations, EU directives and guidance for manufacturers and distributors of human medicines, known as the Orange and Green Guides, compiled by the Medicines and Healthcare products Regulatory Agency (MHRA), are available to buy now. These are an essential purchase for anyone subject to good manufacturing practice (GMP) and good distribution practice (GDP) in Europe. The Orange Guide (Rules and Guidance for Pharmaceutical Manufacturers and Distributors) contains information and legislation relating to the manufacture and distribution of human medicines. The Green Guide (Rules and Guidance for Pharmaceutical Distributors) provides information on the broader distribution. Mark Birse, MHRA GMDP Group Manager, IE&S said: ―The Orange and Green Guides are essential tools in helping companies understand the regulatory environment in which they operate, follow good practice and stay compliant with the law. "This is key to ensuring that safe and high quality medicines for people are being made and distributed, providing the trust needed by patients and healthcare professionals to use them.‖ There are new sections on:  MHRA Innovation Office  MHRA Compliance Management and Inspection Action Group  MHRA‘s risk-based inspection programme naming contract quality control laboratories on a manufacturer‘s licence  the gold standard for Responsible Persons  the application and inspection process for new licences - what to expect
  37. 37. PHARMA UPTODAY 37 The new Green Guide has been updated to incorporate the revised EU guidelines on GDP. In addition there are new sections on:  GDP quality systems  the European Commission Q&A on GDP guidelines  the gold standard for Responsible Persons  a list of persons who can be supplied with medicines by way of wholesale dealing (Human Medicines Regulations 2012)  controls on certain medicinal products  Compliance Management and Inspection Action Group  the application and inspection process for new licences - what to expect  sales representative samples  handling returns of non-defective medicinal products  MHRA‘s risk-based inspection programme  reporting adverse reactions  short-term storage of ambient and refrigerated medicinal products – requirements for a wholesale dealers authorisation  MHRA Innovation Office Both publications provide a new flow chart on registration requirements for UK companies involved in the sourcing and supply of active substances (ASs) to be used in the manufacture of licensed human medicines. Guidance for Industry: User Fee Waivers, Reductions, and Refunds for Drug and Biological Products This guidance provides recommendations to applicants regarding requests for waivers, refunds, and reductions of user fees assessed under sections 735 and 736 of the Federal Food, Drug, and Cosmetic Act (the Act) for drugs, including biological drug products. This guidance is a revision of the draft guidance entitled Draft Interim Guidance Document for Waivers of and Reductions in User Fees (1993 interim guidance), issued July 16, 1993. This revised guidance describes (1) the types of waivers, refunds, and reductions available under the user fee provisions of the Act and (2) the procedures for requesting waivers, refunds, or reductions, and reconsiderations and appeals of FDA decisions on such requests. The revised guidance also provides clarification on related issues such as user fee exemptions for orphan drugs.
  38. 38. PHARMA UPTODAY 38 Guidance Agenda: New & Revised Draft Guidances CDER is Planning to Publish During Calendar Year CATEGORY —Electronic Submissions • NDA and BLA Content for Planning and Conduct of Bioresearch Monitoring Inspections (BIMO) for CDER Submissions • Providing Regulatory Submissions in Electronic Format – Manufacturing Establishment Information • Providing Regulatory Submissions in Electronic Format – Bioanalytical Methods Data Standards CATEGORY —Generics • Acceptability of Draft Package Insert Labeling to Support ANDA Approval • ANDA Submissions Refuse-to-Receive for Typographical Errors and Misplaced Files • Complete Assessments for Type II API DMFs Under GDUFA • Guidance for Industry on GDUFA Completeness Assessment Checklist for Type II API DMFs CATEGORY —Labeling • Indications and Usage Section of Labeling for Human Prescription Drugs and Biological Products – Content and Format • Pediatric Information: Incorporating into Human Prescription Drug and Biological Products Labeling • Product Title and Initial U.S. Approval in the Highlights of Prescribing Information for Human Prescription Drug and Biological Products – Content and Format CATEGORY —Pharmaceutical Quality/CMC • Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base • Appropriate Package Type Terms for Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human Use • Botanical Drug Development • Comparability Protocols for Approved Drugs: Chemistry, Manufacturing, and Controls Information • Development of Near Infrared Spectroscopy (NIR) Procedures • Drug Products Containing Nanomaterials • Elemental Impurities in Drug Products Marketed in the United States • Environmental Assessment: Questions and Answers Regarding Drugs with Hormonal Activity • Established Conditions: Reportable CMC Changes for Approved Drugs and Biologic Products • Liposome Drug Products: CMC, Human Pharmacokinetic and Bioavailability; and Labeling Documentation • Microbiological Quality Consideration in Non-sterile Drug Product Manufacturing • Quality Metrics and Risk-Based Inspections • Specified Biotechnology and Specified Synthetic Biological Products – Annual Report CATEGORY —Pharmaceutical Quality/Manufacturing Standards (CGMP)
  39. 39. PHARMA UPTODAY 39 • CGMP Data Integrity Questions and Answers • Current Good Manufacturing Practice for Outsourcing Facilities (Pharmacy Compounding) • Repackaging of Certain Drug Products by Pharmacies and Outsourcing Facilities Guidance for Industry: Evaluating Drug Effects on the Ability to Operate a Motor Vehicle The purpose of this guidance is to assist pharmaceutical sponsors in the evaluation of the effects of psychoactive drugs on the ability to operate a motor vehicle. Specifically, this guidance addresses the FDA‘s current thinking regarding the FDA-regulated drugs for which such evaluation may be needed, and the types of studies that such an evaluation entails. This draft guidance is intended to serve as a focus for continued discussions among the FDA, pharmaceutical sponsors, the academic community, and the public. This guidance does not address the specific methods or instruments used to collect data on driving ability; rather, the guidance outlines the general principles and goals of such studies.Experience suggests that a number of methods may be suitable for providing the necessary data. Discussions with the appropriate review division about the methods to be used should take place for specific drug development programs. Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid ances/UCM430374.pdf Guidance for Industry: Withdrawn Bioequivalence Recommendations Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid ances/UCM422282.pdf Manual of Policies and Procedures (MAPP) 4001.1 Developing, Issuing and Maintaining Standard Operating Procedures for CDER This MAPP specifies the factors to consider when making a determination on whether to develop a Manual of Policies and Procedures (MAPP) or a Standard Operating Procedure (SOP) when delineating CDER policies and procedures. The MAPP also addresses requirements for maintaining access to, and currency of, SOPs. Source: http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandT obacco/CDER/ManualofPoliciesProcedures/UCM429794.pdf MHRA GMP Data Integrity Definitions and Guidance for Industry January 2015 published Data integrity is fundamental in a pharmaceutical quality system which ensures that medicines are of the required quality. This document provides MHRA guidance on GMP data integrity expectations for the pharmaceutical industry. This guidance is intended to complement existing
  40. 40. PHARMA UPTODAY 40 EU GMP, and should be read in conjunction with national medicines legislation and the GMP standards published in Eudralex volume 4. The data governance system should be integral to the pharmaceutical quality system described in EU GMP chapter 1. The effort and resource assigned to data governance should be commensurate with the risk to product quality, and should also be balanced with other quality assurance resource demands. As such, manufacturers and analytical laboratories are not expected to implement a forensic approach to data checking, but instead design and operate a system which provides an acceptable state of control based on the data integrity risk, and which is fully documented with supporting rationale. Data integrity requirements apply equally to manual (paper) and electronic data. Manufacturers and analytical laboratories should be aware that reverting from automated / computerised to manual / paper-based systems will not in itself remove the need for data integrity controls. This may also constitute a failure to comply with Article 23 of Directive 2001/83/EC, which requires an authorisation holder to take account of scientific and technical progress and enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods. Designing systems to assure data quality and integrity Systems should be designed in a way that encourages compliance with the principles of data integrity. Examples include: • Access to clocks for recording timed events • Accessibility of batch records at locations where activities take place so that ad hoc data recording and later transcription to official records is not necessary • Control over blank paper templates for data recording • User access rights which prevent (or audit trail) data amendments • Automated data capture or printers attached to equipment such as balances • Proximity of printers to relevant activities • Access to sampling points (e.g. for water systems) • Access to raw data for staff performing data checking activities. S10 Photosafety Evaluation of Pharmaceuticals Guidance for Industry The purpose of this guidance is to recommend international standards for photosafety assessment, and to harmonize such assessments that support human clinical trials and marketing authorizations for pharmaceuticals. This guidance includes factors for initiation of and triggers for additional photosafety assessment and should be read in conjunction with ICH M3(R2), section XIV(14) on Photosafety Testing (Ref. 1).3 It should reduce the likelihood that substantial differences in recommendations for photosafety assessment will exist among regions.
  41. 41. PHARMA UPTODAY 41 TGA Guidance on release for supply Release for supply is a mandatory step in manufacture, in which the last manufacturer in the supply chain certifies each batch of medicines produced, before being released to the Australian market. This is to ensure that batch has been produced and quality controlled in compliance with all requirements under the Therapeutic Goods Act 1989. This guidance document, which was developed in consultation with the industry, is published by the TGA to provide industry with guidance on release for supply of medicines. The guidance document consists of two parts:  Part 1: Provides guidance on the general requirements applicable to all manufacturers and sponsors; and  Part 2: provides examples of how the general requirements described in Part 1 can be met for specific areas of manufacture (for example, complementary medicines or sunscreens, or for different supply chains). Part 2 is currently being developed in consultation with industry. Elemental Impurities: USP announces the Date of Entry into Force of Chapters <232> and <2232> On 14 January 2015 - just 2 days after the adoption of the "Guideline for elemental impurities - Q3D" by the CHMP - the USP announced the date for the validity of the General Chapters <232> (Elemental Impurities - Limits) and <2232> (Elemental Contaminants in Dietary Supplements). Both chapters will be applicable as of January, 1st 2018. This date chosen by USP smoothly follows the date of implementation of the "ICH guideline Q3D on elemental impurities" in the European Member States (1st December 2017). At the same time, the USP published a so- called "Notice of Intent to Revise" which announces the revision of the "General Notices section 5.60.30". In these "General Notices" - which formally set the date for the implementation - you can still find the 1st December 2015, whereas the revised version has included the 1st January 2018. Moreover - according to another "Notice of Intent to Revise" - the abrogation of General
  42. 42. PHARMA UPTODAY 42 Chapter <231> (Heavy Metals) will also be postponed from December, 1st 2015 to January, 1st 2018. Thus, the industry is given the opportunity to keep using this Chapter <231> and the numerous referenced monographs until the deadline on January, 1st 2018. Further information can be found in a FAQ document about the Chapters <232>, <233> and <2232>. The justification for USP's approach with regard to the revision of the chapters is described in another FAQ document entitled "Rationale for USP's Proposed Standards for Elemental Impurities".
  43. 43. PHARMA UPTODAY 43 AUDIT FINDINGS - 483 Observations Firm Name 483 Observation Continental Manufacturing Chemist, Inc. Written procedures for sampling and testing plans are not followed for each drug product. Keystone Laboratories, Inc. Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the final specifications prior to release. Agila Specialties Private, Ltd. Investigations of a failure of a batch or any of its components to meet any of its specifications did not extend to other drug products that may have been associated with the specific failure or discrepancy. Vege-Kurl, Inc. dba Joar Labs Written records are not always made of investigations into unexplained discrepancies and the failure of a batch or any of its components to meet specifications. Bristol-Myers Squibb Co., Inc. Buildings used in the manufacture, processing, packing or holding of drug products are not free of infestation by rodents, birds, insects and other vermin. Cadila Healthcare Limited Written records of investigation of a drug complaint do not include the findings of the investigation and the follow-up. Community Blood Center of Greater Kansas City There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Gopers Int, LLC There is no quality control unit. Laboratorio Magnachem International, S.A.L. Laboratory controls do not include the establishment of scientifically sound and appropriate sampling plans designed to assure that components and drug products conform to appropriate standards of identity, strength, quality and purity.
  44. 44. PHARMA UPTODAY 44 UCSF Home Therapy Services Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process. Alza Corp. Written production and control procedures are not followed in the execution of production and process control functions. GlaxoSmithKline Biologicals Inadequate Quality Unit Oversight since 2007 to identify adverse trend of molds, investigate adverse trends, and implement corrective actions to prevent recurrences of molds in the manufacturing environment. Micro Connection Enterprises, Inc. Written procedures are not established and followed for evaluations conducted at least annually to review records associated with a representative number of batches, whether approved or rejected. International Medication Systems Ltd. In-process specifications are not derived from previous acceptable process average and process variability where possible. Custompax, Inc. dba Vitaganic You did not conduct appropriate tests or examinations to determine compliance with the specifications established for identity, purity, strength, and composition. Top Drug 483 Observations Lax procedural documentation in quality control units topped the list of reasons why drugmakers received Form 483s for the ninth consecutive year, while poor laboratory controls jumped to second place from fourth in the annual rankings of inspection observations. The data come from the FDA‘s annual statistical report of 2,855 domestic and foreign drug inspections it scheduled to conduct from Oct. 1, 2013, through Sept. 30, 2014. During this period, the FDA issued 645 Form 483s to drugmakers, down from 690 in the previous fiscal year and 787 in 2012. The top 10 observations in drug 483s were: • Responsibilities and procedures for quality control units aren‘t in writing or fully followed (cited in 145 forms, down from 155 in 2013); • Laboratory controls aren‘t scientifically sound or appropriate (109, up from 99); • Failure to thoroughly review a batch failure and whether it was already distributed (94, down from 131); • No written procedures for production and process controls (87, down from 106). • Written procedures aren‘t established for cleaning and maintenance of equipment (72, down from 77);
  45. 45. PHARMA UPTODAY 45 • Procedures to prevent microbiological contamination of sterile drug products aren‘t established, written or followed. Compounding pharmacies are typically cited for this observation (72, down from 76); • Testing and release of drug products doesn‘t include appropriate laboratory determination of conformance to specifications for the active ingredient (64, down from 66); • Equipment and utensils aren‘t cleaned or maintained (63, down from 71); • Routine equipment maintenance isn‘t performed according to a written program (54, down from 56); and • No written testing program to assess stability (51, down from 62).
  46. 46. PHARMA UPTODAY 46 AUDIT FINDINGS - EMA Non Compliance Reports Non-Compliance Report: Wockhardt Limited, Aurangabad Nature of non-compliance : 1. A critical deficiency was cited with regards to data integrity of GMP records, entries were seen to be made when personnel were not present on site, documentation was seen that was not completed contemporaneously despite appearing to be completed in this manner. 2. A second critical deficiency was cited regarding potential product contamination, this included the use of inappropriate materials close to product e.g. asbestos coated PTFE seals for centrifuge manways. 3. A major deficiency was cited with regards to equipment and facility, maintenance, design and qualification. Examples included, inappropriate pressure differentials that were not in line with the original design but had not been changed using change control, cleaning validation that was not sufficiently robust to confirm cleaning practices and maintenance issues, such as the failure to spark test glass lined reactor vessels for integrity especially following maintenance. Non-Compliance Report of AGEPHA, Anstalt zur gewerblichen Produktion von Heilmitteln und Arzneiwaren GmbH, Austria Nature of non-compliance : The inspection was performed by 3 GMP-Inspectors on 05th of March 2014. 11 GMP-deficiencies were observed; out of these 8 were rated as major. After three responses from the company dating 14th of May 2014, 22nd of July 2014 and 22nd of August 2014, two major deficiencies still remain unsolved. One manufacturing process has not been revalidated after severe process changes (frequent quality defects of this product have been reported to the inspectorate ). The company failed to prove that all relevant analytical methods used have been validated by the QC department. Inappropriate reference material has been used – the company could not deliver proof that the current reference material is suitable for the intended use. Non-Compliance Report: North China Pharmaceutical Group Semisyntech Co., Ltd, China Nature of non-compliance : Overall, 17 deficiencies were observed during the inspection, including 2 Critical and 4 Major deficiencies:
  47. 47. PHARMA UPTODAY 47 [Critical 1] Manipulation and falsification of GMP documents (rewriting of records with change of content, an inconsistency of signatures and date in many records, etc.) were observed in different department; [Critical 2] Lack of data integrity in the QC laboratory (No access control, inadequate traceability and archiving practices, no audit trail, no restriction on the deleting of data, etc.) and falsification of the analytical results for residual solvents; [Major 1] Risk of contamination in grade B area; [Major 2] The change control related to (i)- the change of the identification number of some manufacturing equipment and (ii)- the merger project of NCPC semisynthec and Hebei Huari was found deficient; [Major 3] Lack of documentation management, control, and retention of superseded or obsolete version; [Major 4] The company personnel was not adequately trained in GMPs as evidenced by the critical and major deficiencies identified during this inspection. Check your area for …. • Are training records are …  up-to-date,  securely filed  available for review as necessary?  easily retrieved?

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