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Pharma Uptoday Monthly Magazine volume 4 issue jul 2014

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Celebrating Successful completion of one year
"Happy anniversary… Pharma Uptoday"

Thanks a lot to all members & Viewers.
To recap the previous month's pharma highlights to Pharma Uptoday members, Monthly magazine Volume 4 has been released with

News Uptoday
New Guidelines
Audit Findings
Regulation of the Month

Published in: Healthcare
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Pharma Uptoday Monthly Magazine volume 4 issue jul 2014

  1. 1. Celebrating Successful completion of one year Happy anniversary… VOLUME: 4 - ISSUE: JUL 2014 | PHARMA UPTODAY For wishes, feedback, suggestions, queries, requirements & complaints write to us on “pharmauptoday@gmail.com”
  2. 2. PHARMA UPTODAY 2 Inside This Issue 3 News Uptoday 12 New Guidelines 18 Audit Findings 483 Observations WHO – NOC Microlabs, Hosur Warning Letters Apotex Pharmachem India Pvt Ltd Tianjin Zhongan Pharmaceutical, China ID Biomedical Corp., a subsidary of GSK Biologicals Lee and Company Pharmacy Creations, NJ EMA Non-Compliance Reports MOORFIELDS PHARMACEUTICALS, United Kingdom SIMS, Italy WOCKHARDT LIMITED, India Yung Shin Pharmaceutical Ind Co Ltd, Taiwan 27 Regulations of the Month § 211.165 Testing and release for distribution § 211.166 Stability testing
  3. 3. PHARMA UPTODAY 3 News Uptoday USFDA inspects Divis Laboratories' facility Drug firm Divis Laboratories' facility near Visakhapatnam has been inspected by the US drug regulator early this month for its "custom manufactured product". The Unit II at village Chippada near Visakhapatnam has had an inspection by the United States Food and Drug Administration (USFDA) with no major observations, Divis Laboratories said. "The audit concluded with one observation primarily about further improvement of existing procedure. The purpose of this inspection was for custom manufactured product," it added. Divis undertakes custom manufacture of active pharmaceutical ingredients (APIs) and advanced intermediates. EU lifts drug export ban from Ranbaxy's Toansa plant European health regulator on Thursday lifted suspension imposed on export of drugs produced at Ranbaxy's Toansa plant to the EU stating medicines produced at the site posed no risk to public health despite having a number of manufacturing deficiencies. In a statement, the European Medicines Agency (EMA) said European regulatory authorities have finalised their assessment of reported non-compliance with Good Manufacturing Practice (GMP) at the Toansa plant. "There were a number of GMP deficiencies at the concerned site, assessment of all available information has reassured European regulators that there has been no risk to public health from these deficiencies," it said. As a consequence, the EU authorities will reinstate the GMP certificate which was suspended in January 2014. The certificate will be re-entered into EudraGMDP, the EU database that contains GMP certificates, EMA added. It further said: "Patients should continue to take their medicines as prescribed by their healthcare professional." The inspection team concluded that there was no evidence that any medicines on the EU market that have an active pharmaceutical ingredient manufactured in Toansa were of unacceptable quality or presented a risk to the health of patients taking them, it said. The regulator added: "European regulatory authorities have identified the need to keep the Toansa site under close supervision and this will be done in collaboration with India and other regulatory authorities around the globe". Glenmark opens plant in Switzerland Mumbai-headquartered pharma company, Glenmark Pharmaceuticals, has set up a manufacturing facility in Switzerland for the supply of clinical trial material. The drug maker has opened the cGMP compliant monoclonal anti-body manufacturing facility in La Chaux-de- Fonds, Switzerland, through its wholly-owned subsidiary. The new facility supplements Glenmark’s existing in- house discovery and development capabilities and will supply material for clinical development.
  4. 4. PHARMA UPTODAY 4 The plant has been designed for the use of single-use bioreactor system and also houses a suite for manufacturing cell bank. The facility claims to be fully compliant with quality, environmental and safety standards for developing clinical trial material. The existing Swiss research centre focuses on developing novel biologic entities for the treatment of pain, inflammatory, oncologic and respiratory conditions and has 69 employees. Glenmark has been doing cutting edge work in the area of novel monoclonal antibodies and have several monoclonal antibody candidates and bi-specific antibodies in the pipeline. The facility will help them bring these antibodies to the clinic faster. High Court Lifts Stay on Sun Pharma's $3.2 Billion Ranbaxy Takeover The Andhra Pradesh High Court on Saturday lifted a temporary stay it imposed on generic drugmaker Sun Pharmaceutical Industries Ltd's $3.2 billion takeover of Ranbaxy Laboratories Ltd, a lawyer involved in the case said, paving the way for both companies to complete the deal. The court last month ordered an "interim status quo" on the deal, pending a decision on a petition for a probe into alleged insider trading. The petition was filed in late April by two individuals who requested that the court ask the market regulator SEBI and the two main stock exchanges to halt the deal and order a probe. "The court has vacated the stay order on the deal," Vivek Reddy, lawyer for the petitioners. Ranbaxy shares jumped 24 per cent and trading volume tripled in three sessions ahead of the companies' announcement on April 7 that Sun Pharma would buy the loss-making company from Japan's Daiichi Sankyo Ltd. Sun Pharma declined to comment when contacted by Reuters, while Ranbaxy spokesmen did not immediately respond to an email requesting comment. Companies now required to update, complete and improve quality of information on authorised medicines submitted to the European Medicines Agency From today, the European Medicines Agency requires marketing-authorisation holders to update the information on authorised medicines that they have submitted in accordance with Article 57(2) of the 2010 pharmacovigilance legislation. This includes completing previously submitted information with additional data elements included in the new data-submission format, bringing medicine information up–to-date, and checking that the quality of the information is in line with the updated reporting requirements. Companies need to complete this process by the end of 2014. The additional elements that are now required include: • the details of the legal basis of the marketing authorisation; • a description of the medicinal product type based on controlled vocabularies; • information on the authorised pharmaceutical form and before reconstitution into the ‘administered’ pharmaceutical form;
  5. 5. PHARMA UPTODAY 5 • a description of the size of the marketing-authorisation-holder company. From today, the data submission system will only accept submissions that are in line with the updated data- submission format. From July 2014, the Agency is planning to begin a systematic review of the quality and integrity of the information submitted, to ensure that it is accurate and up-to-date. This information on medicines is being used to support pharmacovigilance data analysis, to facilitate medicines regulation and fulfil regulatory actions and legal obligations, and to strengthen communication with the Agency’s stakeholders and partners. By streamlining the identification of products relevant to pharmacovigilance procedures, this database is expected to simplify adverse reaction reporting for marketing- authorisation holders and ensure that fees are calculated accurately. Since January 2014, the Agency has been releasing guidance documents to support marketing-authorisation holders in these tasks. These include updates to the legal notice, detailed technical guidance, a data quality control methodology and controlled vocabularies. The Agency has also published two new guidance documents today concerning the splitting of the full presentation names and substance names best practice. In addition to completing previously submitted information, marketing-authorisation holders need to continue to submit information on new marketing authorisations within 15 calendar days from the date of notification of the granting of the marketing authorisation by a regulatory authority. If companies using the EudraVigilance Gateway to submit data cannot provide this information within this timeframe because of the schema changes, they should inform the Agency of their expected submission plan by emailing art57submissionplan@ema.europa.eu and provide their name, headquarter ID, volume of data and timeline for submission. The Agency has been working closely with representatives of European pharmaceutical-industry associations on the development of these measures through the Joint Implementation Working Group (IWG). The Group has endorsed all of the aspects related to the planning of and guidance on the data maintenance submission process. In line with Article 57(2) of the 2010 pharmacovigilance legislation, all holders of marketing authorisations for medicines in the European Union (EU) must submit information to the European Medicines Agency on all medicines authorised for use in the EU and keep this information up-to-date. This includes: • nationally authorised medicinal products (NAPs); • centrally authorised medicinal products (CAPs); • mutually recognised medicinal products (MRPs); • decentrally authorised medicinal products (DCPs). Marketing authorisation holders are also required to submit to the Agency information on all medicines for which they hold a marketing authorisation in European Economic Area (EEA) countries outside the EU (i.e. Iceland, Liechtenstein and Norway) since the pharmacovigilance legislation has been incorporated into the EEA agreement. Marketing-authorisation holders were initially required to submit information on all human medicines authorised in the EU by 2 July 2012. Since July 2012, marketing-authorisation holders have also had to submit information on new marketing authorisations granted after 2 July 2012.
  6. 6. PHARMA UPTODAY 6 Granules India's paracetamol facility passes USFDA inspection Drug firm Granules India's paracetamol manufacturing facility at Bonthapally in Andhra Pradesh has passed an inspection by the US health regulator. The company's paracetamol facility has successfully passed a United States Food and Drug Administration (USFDA) inspection without any '483 observations', Granules India said in a filing to the BSE. "The facility has the world's largest single active pharmaceutical ingredient (API) production line by volume," it added. .. An FDA Form 483 is issued to the firm's management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgement may constitute violations of the Food Drug and Cosmetic (FD&C) Act and other related acts. The company's four API facilities have passed the USFDA inspections in the past 12 months, Granules India said. Hyderabad-based Granules India has facilities for APIs, pharmaceutical formulation intermediates (PF Is) and finished dosages, serving customers in over 60 countries. India thwarts Big Pharma push at WHO assembly India has successfully thwarted Big Pharma's attempt to influence norm-setting for medicines in the resolution passed recently at the World Health Assembly in Geneva. India, along with several other countries, also objected to the World Health Organization's (WHO) involvement with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), a pharma industry initiative. Civil society organizations working for greater access to medicines are pleased with the Indian initiative. According to them, "harmonization", in this context, was just a euphemism for setting of industry-led standards which favour the interests of transnational pharmaceutical corporations and their push to weaken competition from generic medicines. The original draft of the resolution has several references to "harmonization of technical requirements for registrations of pharmaceuticals for human use" by developing appropriate norms and standards "taking into account the standards created by existing regional and international initiatives". India got all such references dropped before the resolution on regulatory system strengthening for medical products was adopted. FDA Releases Strategic Priorities Document Request for Comments on the Food and Drug Administration Fiscal Year 2014-2018 Strategic Priorities Document; Request for Comments The Food and Drug Administration (FDA) is seeking public comments on its draft Strategic Priorities Fiscal Year (FY) 2014-2018 document. FDA has identified these cross-cutting strategic priorities and core mission goals that will guide its efforts to achieve its public health mission. FDA is seeking public comment to help further refine these priorities and goals.
  7. 7. PHARMA UPTODAY 7 According to Dr. Hamburg, “we are in the beginning of a new era for drug safety where protecting public health means that FDA’s responsibility doesn’t end when we grant a product market approval; that is merely the first check point in ensuring safety.” FDA has a three-pronged plan to achieve its mission to ensure consumer access to safe and effective drugs. They are illustrated by the long-term objectives captured in Table 3 below and the key strategies associated with each objective. Summary of Long-Term Objectives for Human Drugs Long-Term Objectives Key Strategies 3.2.1.1 Promote public health by ensuring the availability of safe and effective new drugs • Identify and develop new scientific methods, models, and tools to improve the quality, safety, predictability, and efficiency of new drug development • Conduct rigorous science-based premarket review to ensure that drugs that will be marketed to the public are safe and effective • Ensure patient awareness of drug benefits and risks through effective communication of drug information 3.2.1.2 Protect public health by ensuring the quality and integrity of marketed drug products • Secure the global supply chain to ensure that drugs are being manufactured and distributed to conform to established quality standards • Improve drug quality oversight capacity through expanded use of risk-based methods • Ensure public awareness of drug quality and integrity issues through effective consumer communications 3.2.1.3 Protect public health by promoting the safe use of marketed drugs • Conduct postmarket surveillance to ensure early detection of new safety signals • Conduct rigorous studies to understand new drug safety signals and effectively manage emerging risks • Ensure patient and health professional awareness of drug risks and parameters for safe use • Oversee drug promotion and marketing to ensure that marketed drug labeling and advertising are truthful and not misleading Source: https://www.federalregister.gov/articles/2014/07/01/2014-15374/office-of-the-commissioner-request- for-comments-on-the-food-and-drug-administration-fiscal-year http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm246751.htm#table3 http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm227527.htm
  8. 8. PHARMA UPTODAY 8 Tokyo prosecutor to charge Novartis Japan unit, ex-employee over manipulating data Tokyo prosecutors said on Tuesday they will charge the Japanese unit of Novartis AG and a former employee in connection with allegations of data manipulation in promoting its best-selling blood pressure drug Diovan. The prosecutors office said in a statement that it had decided to arrest Nobuo Shiraishi on allegations he gave false data to researchers whose work was used for advertising. Shiraishi was initially detained in June. The prosecutor also said that Novartis Pharma KK, the Swiss drugmaker's wholly owned local subsidiary, will be charged in connection with the case under a provision that alleges responsibility for failing to oversee an employee. Novartis said it was cooperating with an ongoing investigation by the Japanese authorities and had taken corrective measures, including replacing senior management of its Japan subsidiary. "Novartis and NPKK have already undertaken decisive action to address problems with the company's Investigator-Initiated Trial (IIT) research programmes in Japan," David Epstein, the company's global division head, said in a statement. "We are committed to changing the culture at Novartis Pharma KK and demonstrating ethical leadership among pharmaceutical companies in Japan," he added. Any individual found guilty of exaggerated advertising of drugs in Japan can be punished with up to two years in prison or a fine of as much as 2 million yen ($19,700) or both. ($1 = 101.4600 Japanese Yen) Source : http://www.reuters.com/article/2014/07/01/novartis-japan-idUSL4N0PC1X220140701 TGA publishes Summary of fees and charges at 1 July 2014 Please find the complete version of Summary of fees and charges at 1 July 2014 published by TGA in the attachment. Source: http://www.tga.gov.au/about/fees-140701.htm#.U7LpzvmSwix TGA clarifies Australian eCTD submissions The TGA is implementing software to validate, review and process electronic applications for the entry of registered medicines on to the Australian Register of Therapeutic Goods (ARTG). Other regulated products will not be affected. This software can be used for submissions in both electronic Common Technical Document (eCTD) and non eCTD (NeeS) formats. Currently we are working with industry representatives to identify suitable eCTD pilot submissions to test various aspects of the TGA electronic submission system before fully adopting the software in 2015. We are looking to test the following application types:
  9. 9. PHARMA UPTODAY 9 • new chemical entity • major variations to a prescription medicine (both with and without baseline) • generic medicine. Testing will also include submissions prepared with different publishing tools and may cross areas such as OTC, complementary and prescription medicines and master files. For more information browse: http://www.tga.gov.au/industry/esubmissions.htm#.U7Lo_fmSwiw FDA seeks permanent injunction against California pharmaceutical company On June 25, the U.S. Department of Justice, at the request of the U.S. Food and Drug Administration, filed a complaint for permanent injunction in the U.S. District Court for the Central District of California against Laclede, Inc. (Laclede) of Rancho Dominguez, California, and its president, Michael A. Pellico. The complaint claims that Laclede illegally distributes over-the-counter vaginal drug products without required FDA approval. According to the complaint, Laclede is in violation of the Federal Food, Drug, and Cosmetic Act for introducing unapproved and improperly labeled (misbranded) drugs for sale across the country. The prebiotic vaginal products named in the complaint are: • Luvena Prebiotic Vaginal Moisturizer and Lubricant • Luvena Prebiotic Enhanced Personal Lubricant • Luvena Prebiotic Feminine Wipes • Luvena Prebiotic Daily Therapeutic Wash The complaint requests, among other things, that the court issue a permanent injunction order requiring Laclede to cease distribution of these drug products until the company obtains an approved new drug application from the FDA or until all drug claims have been removed from the products’ labels, marketing materials, and any websites controlled by or related to Laclede. “The drug approval process is critical to ensuring that drugs are safe and effective for their intended uses,” said Carol Bennett, acting director of the Office of Compliance in the FDA’s Center for Drug Evaluation and Research. “The FDA will take swift action when companies bypass this important process established to protect consumers from harmful products.” Since 2010, the FDA has repeatedly told the company that it must obtain the FDA’s approval before selling its drug products. According to the complaint, the company subsequently marketed and distributed the unapproved drug products, despite the FDA’s warnings. The FDA, an agency within the U.S. Department of Health and Human Services, promotes and protects the public health by, among other things, assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the
  10. 10. PHARMA UPTODAY 10 safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products. Source: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403561.htm & http://www.justi ce.gov/opa/pr/2014/July/14-civ-687.html Indian Pharma Industry Worried About Chinese APIs The India Pharmaceuticals Association (IPA) urged the Finance Ministry to come up with a policy framework with regard to incentives to drug innovation and ease dependence on import of essential APIs (Active pharma ingredients) from China. Currently, India is dependent on China for import of some of the API and it may become a serious concern, if problems arises in the supply-chain system, IPA President K Satish Reddy, told reporters here today. "If there is breakdown in the supply chain for whatever reasons in China, we will suffer, because India does not have the capacity to meet those kind of need and it will lead to higher costs," he explained. A policy frame work can ease the dependence on China for some of the essential drugs, he added. The association also suggested that government should concentrate on setting up industrial clusters to manufacture some of the essential bulk drugs to reduce dependence on the neighbouring country. It also demanded that weighted deduction of 200 per cent of R&D expenses should be increased to 250 per cent in the upcoming union Budget. “So if we would like to spur innovation in this country we expect a policy framework which would incentives innovation," Reddy said, who is chairman of Dr Reddy's Laboratories.
  11. 11. Celebrating Successful completion of one year Happy anniversary… category Non Compliance Reports Basics Quality tools Webinars PHARMA UPTODAY News Articles Warning letters Presentation Guideline Regulation Drug category VIdeos For wishes, feedback, suggestions, queries, requirements & complaints write to us on “pharmauptoday@gmail.com PHARMA UPTODAY 11 Warning letters 483's GMP Presentation For wishes, feedback, suggestions, queries, aints write to us on pharmauptoday@gmail.com”
  12. 12. PHARMA UPTODAY 12 New Guidelines FDA releases Draft Guidance for Industry: Providing Submissions in Electronic Format- Postmarketing Safety Report This is one in a series of guidance documents intended to assist applicants making certain regulatory submissions in electronic format to the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) in the Food and Drug Administration (FDA or the Agency). This draft guidance revises and replaces the draft guidance for industry entitled Providing Regulatory Submissions in Electronic Format – Postmarketing Individual Case Safety Reports, issued on June 12, 2008 (73 FR 33436). It provides general information pertaining to electronic submission of postmarketing safety reports (individual case safety reports (ICSRs), attachments to ICSRs (ICSR attachments) and other postmarketing safety reports) for the following products: • Drug products marketed for human use with approved new drug applications (NDAs) 26 and abbreviated new drug applications (ANDAs) • Prescription drug products marketed for human use without an approved NDA or ANDA • Biological products, other than vaccines, marketed for human use with approved biologic license applications (BLAs) • Nonprescription (over-the-counter or OTC) human drug products marketed without an approved application. Source: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccine s/ucm074850.htm FDA releases draft Guidance for Industry on "Drug Supply Chain Security Act Implementation: Identification of Suspect Product and Notification" This guidance is intended to aid trading partners (manufacturers, repackagers, wholesale distributors, or dispensers) in identifying a suspect product and terminating notifications regarding illegitimate product. Beginning on January 1, 2015, a trading partner who determines that a product in its possession or control is an illegitimate product must notify the Food and Drug Administration (FDA or Agency) and certain immediate trading partners under section 582 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360eee), as added by the Drug Supply Chain Security Act (DSCSA). This guidance identifies specific scenarios that could significantly increase the risk of a suspect product entering the pharmaceutical distribution supply chain; provides recommendations on how trading partners can identify the product and determine whether the product is a suspect product as soon as practicable; and sets forth the process by which trading partners should notify FDA of illegitimate product and how they must terminate the notifications, in consultation with FDA. Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM400470.pdf
  13. 13. PHARMA UPTODAY 13 US FDA Releases draft guidance on "ANDA Submissions — Content and Format of Abbreviated New Drug Applications" This guidance is intended to assist applicants in preparing abbreviated new drug applications (ANDAs) for submission to the Food and Drug Administration (FDA) under section 505(j) of the Federal Food, Drug and Cosmetic Act (the FD&C Act) (21 U.S.C. 355(j)). This guidance details the information to be provided in each section of the Common Technical Document (CTD) format for human pharmaceutical product applications and identifies supporting guidance documents and recommendations issued by FDA to assist in preparing the submission. This guidance does not address the fee structure or payment of obligations under the Generic Drug User Fee Amendments (GDUFA) and does not address the submission and assessment of drug master files (DMFs), amendments to original ANDAs, and changes being effected or prior approval supplements. This guidance identifies the information an applicant should include to ensure that a complete, high-quality application is submitted to FDA. FDA has previously published guidance on the filing process, including the refuse- to-receive standards, which should be reviewed thoroughly to avoid common deficiencies found in ANDA submissions. Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM400630.pdf US FDA releases "Guidance for Industry: Q4B Annex 6: Uniformity of Dosage Units General Chapter" This annex is one in a series of guidance documents that describe the evaluations and recommendations by the Q4B Expert Working Group (EWG) of selected pharmacopoeial texts to facilitate their recognition by regulatory authorities for use as interchangeable in the ICH regions. Implementation of the Q4B annexes is intended to avoid redundant testing by industry. For general information on the Q4B process, the reader is referred to the core guidance Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions. This annex is the result of the Q4B process for the Uniformity of Dosage Units General Chapter. The proposed texts were submitted by the Pharmacopoeial Discussion Group (PDG). FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. Q4B OUTCOME (2) A. Analytical Procedures (2.1) The ICH Steering Committee, based on the evaluation by the Q4B Expert Working Group (EWG), recommends that the official pharmacopoeial texts, Ph. Eur. 2.9.40. Uniformity of
  14. 14. PHARMA UPTODAY 14 Dosage Units, JP 6.02 Uniformity of Dosage Units, and USP General Chapter <905> Uniformity of Dosage Units, can be used as interchangeable in the ICH regions subject to the following conditions: 1. (2.1.1) Unless the 25 milligrams (mg)/25% threshold limit is met, the use of the Mass/Weight Variation test as an alternative test for Content Uniformity is not considered interchangeable in all ICH regions. 2. (2.1.2) For specific dosage forms that appear in local text in the pharmacopoeias by enclosing the text in black diamond symbols, application of the Uniformity of Dosage Units test is not considered interchangeable in all ICH regions. 3. (2.1.3) If a correction factor is called for when different procedures are used for assay of the preparation and for the Content Uniformity Test, the correction factor should be specified and justified in the application dossier. B. Acceptance Criteria (2.2) The evaluated texts did not contain acceptance criteria. Endotoxin limits should be specified in the application dossier unless otherwise specified in an individual monograph. TIMING OF ANNEX IMPLEMENTATION (3) When this annex is implemented (incorporated into the regulatory process at ICH Step 5) in a region, it can be used in that region. Timing might differ for each region. Source : http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM085364.pdf TGA joins EDQM's CEP assessment process The Therapeutic Goods Administration (TGA) is set to strengthen its collaboration with the European Directorate for the Quality of Medicines and HealthCare (EDQM). In May 2014 Australia was accepted as an assessor in the EDQM's procedure for the Certification of Suitability to the monographs of the European Pharmacopoeia (CEPs). The certification procedure for CEPs assesses the suitability of monographs to control the chemical purity, microbiological quality and transmissible spongiform encephalopathy (TSE) risk (if relevant) for any substance covered by a European Pharmacopoeia monograph. TGA assessors will take part in the scientific assessment of applications submitted by manufacturers to obtain a CEP. This will allow Australia to share information, skills and experience with our international colleagues leading to more informed and consistent regulatory decisions internationally. Australia is one of a handful of countries outside of European member states that recognises CEPs in its evaluation processes for generic medicines. Working together with regulators from different jurisdictions to develop common standards, guidelines and regulatory requirements will reduce the time to market for therapeutic products ensuring Australians have access to quality medicines in a timely manner. URL: http://www.tga.gov.au/about/international-edqm-cep.htm
  15. 15. PHARMA UPTODAY 15 EMA Publishes New Guidance for Qualified Person's Declaration on GMP Compliance of API A regulatory order to stop sales from Chicago based unit means the company stands to lose half its revenue Just two years after emerging from a financial crisis caused by derivative bets gone awry, Mumbai-based drug maker Wockhardt Ltd is confronting more trouble—this time in the form of penal action by the US regulator. The US Food and Drug Administration (FDA), which last year banned generic drug imports from Wockhardt’s plants at Waluj and Chikalthana in Maharashtra citing flawed manufacturing processes, on 27 May voiced concern about production quality at the company’s US unit. An FDA warning letter or order to stop sales to the Chicago-based unit, Morton Groves Pharmaceuticals Inc., will lead to a complete erosion of US sales for the company that in the year ended 31 March 2013 derived half its overall revenue of $1.03 billion from the world’s biggest drug market. In the year just gone by, revenue fell 26% because of the import ban on its generic sales. According to a US-based manufacturing compliance expert, who didn’t want to be named, the FDA’s recent observations about the Chicago plant would necessarily be followed up by a warning letter, which effectively is a sales ban on the factory. Before the import ban on the plants in Maharashtra, the Chicago facility contributed half of Wockhardt’s US revenue. Wockhardt declined to comment for this story. A detailed questionnaire sent to chairman Habil Khorakiwala and the company’s spokesperson on 7 June remained unanswered at the time of going to press on Wednesday. Wockhardt’s management said at an analyst meeting last month that it had responded to the FDA’s notice on Morton Grove, and that if the regulator was not satisfied with the response, it could ban production from the Chicago-based unit. EDQM Publishes Annual Report for the year 2013 The EDQM has just published its 2013 Annual Report. The report is an opportunity to review the different activities of the past year and reflect on what the EDQM accomplished and developed. In her foreword, EDQMDirector, Dr Susanne Keitel, comments on the year’s events, achievements, and thanks all involved for their dedication, expertise and support. Read the 2013 annual report More about the EDQM Vision, Mission and Values Ranbaxy's Gurgaon unit might get to sell drugs in US Ranbaxy Laboratories had filed applications seeking to sell drugs in the US made at its Gurgaon plant, which is not on among those barred by the the US Food and Drug Administration (FDA), according to a company executive who did not wish to be named. “Ranbaxy has five manufacturing facilities in India that are registered with the FDA: Paonta Sahib, Mohali, Toansa, Gurgaon, and Dewas,” the US drug regulator’s spokesperson told Business Standard. Four of these are barred from supplying medicines to the US market but the Gurgaon plant is on the FDA approved list.
  16. 16. PHARMA UPTODAY 16 A Ranbaxy executive said Abbreviated New Drug Applications (ANDAs) were recently filed from the Gurgaon facility seeking the FDA’s approval to sell generic medicines in the US. “The FDA does not discuss communications with pharmaceutical companies,” the FDA spokesperson said when asked about Ranbaxy’s filings from its Gurgaon plant. FDA Publishes New Draft documents - Guidance for Industry: Current Good Manufacturing Practice — Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act This interim guidance describes FDA’s expectations regarding compliance with current good manufacturing practice (CGMP) requirements for facilities that compound human drugs and register with FDA as outsourcing facilities under section 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Under section 501(a)(2)(B) of the FD&C Act, a drug is deemed to be adulterated if it is not produced in accordance with CGMP. FDA’s regulations regarding CGMP requirements for the preparation of drug products have been established in 21 CFR parts 210 and 211. FDA intends to promulgate more specific CGMP regulations for outsourcing facilities. Until final regulations are promulgated, this guidance describes FDA’s expectations regarding outsourcing facilities and the CGMP requirements in 21 CFR parts 210 and 211 during this interim period. This guidance is only applicable to drugs compounded in accordance with section 503B. (Refer enclosed Guidance document) Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM403 496.pdf
  17. 17. PHARMA UPTODAY 17 Celebrating Successful completion of one year Happy anniversary… Top Pharma Uptoday presentations of last year: 1. Code of Federal Regulations Parts 210 and 211 (GMP) 2. Analytical method validation approaches from Development to Launch 3. Dissolution 4. Laboratory Errors 5. Understand The Importance of Each Step to minimise Errors 6. Free Resources & Tools from USP 7. Tablets I, II & III 8. Principles of Spectroscopy 9. Management of GMP Documentation 10. Measuring Volume 11. Good Chromatographic Practices 12. Peak Integration for Chromatography 13. Data integrity 14. Chromatography Data System (CDS) To get the presentations, write a mail to us on “pharmauptoday@gmail.com” Pharma uptoday is having about 270 subscribers working for different pharma companies like Ranbaxy, Novartis, Sun pharma, Dr.Reddy’s, Mylan, Aurobindo, Apotex, Hospira, Lupin, Vimta, Diacel, Alphamed, Hetero, Glenmark, Microlabs, Lauruslabs, Amneal india, Mdrl, Vivimed Labs etc.
  18. 18. PHARMA UPTODAY 18 AUDIT FINDINGS - 483 Observations Firm Name 483 Observation WSM Investments LLC dba Topco Sales Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the final specifications and identity and strength of each active ingredient prior to release AMRI Rensselaer Written procedures describing the receipt, identification, quarantine and storage of returned materials are not followed. Amneal Pharmaceuticals LLC An NDA Field Alert Report was not submitted within three working days of receipt of information concerning a failure of one or more distributed batches of a drug to meet the specifications established for it in the application. Mission Pharmacal Co. Written procedures are not established that describe the in-process controls and tests to be conducted on appropriate samples of in-process materials of each batch. Advance Pharmaceuticals, Inc. The responsibilities and procedures applicable to the quality control unit are not fully followed. Omega & Delta Co., Inc. The responsibilities and procedures applicable to the quality control unit are not fully followed. Raphe Healthcare, Inc., dba Raphe' Pharmaceutiques There is no quality control unit. Crown Laboratories, Inc. The written stability testing program is not followed. Dixon Investments, Inc. The responsibilities and procedures applicable to the quality control unit are not fully followed CBI Laboratories, Inc. There is a failure to thoroughly review any unexplained discrepancy and 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 IBA Molecular North America, Inc. You did not oversee production operations in a manner to ensure that each PET drug meets the quality and purity characteristics that it is supposed to have. Laureate Biopharmaceuticals Services, Inc. The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed.
  19. 19. PHARMA UPTODAY 19 AUDIT FINDINGS - WHO - Notice of Concern (NOC) Microlabs, Hosur (dated 30 May 2014): (i) Failed to establish, implement and maintain policies, systems, procedures and controls to ensure the reliability, attribution and integrity of data. Laboratory instruments were not appropriately used and controlled. a. 5 HPLCs were used with software audit trail not enabled. b. No audit trail of manual integration of the peak reflected on the electronic chromatograms as “bb”. c. The printouts of the chromatograms did not reflect the integration type (BB, bb etc.) d. There was no documentation of a justification for the manual integration. e. HPLC Software system administrator had provided misleading information. f. Atleast 5 HPLCs were used with the date and time function unlocked. (standalone systems). g. Common password had been used by laboratoty personnel, reflecting only “labused / analyst” in the audit trail. Raw data and the individual activities to the specific analyst are therefore not attributed to a specific analyst. h. Trial system suitability performed was not included in the sample analysis record. i. Analysts were allowed to and were able to delete files without control and documentation justification. j. Responsible IT person was not able to answer any questions on backup, audit trails and password management. (ii) Failed to appropriately ensure the integrity and reliability of stability data produced by the Stability Section. a. Audit trails of several HPLC systems in the stability section were not enabled. b. Stability report for one batch could not be located during the inspection. c. Electronic analysis data reviewed on several HPLC systems was not attributable to the responsible analyst as the user was logged in as “lab user” and not identified by his/her unique username and password. d. Failed to appropriately secure the data obtained from the stability testing. e. Inconsistency in timings observed between analytical reports and the audit trail data. f. While manual integration was performed to integrate impurity peaks, there was no procedure available on manual integration. (iii) Analytical Work Reports (AWRs) were not appropriately issued by the laboratory QA section and different stages of preparation od samples, solutions, buffers and testing were not always recorded at the time of analysis; and results were not processed in a timely manner. a. AWRs were not always completed at the time of sample preparation / weighing of sample / standard preparation of buffer solution, mobile phase, impurity solution, system suitability solution, test solution, standard solution. b. In several AWRs, results were recorded by analysts several days before the inspection, but these results/calculations were not appropriately recorded as for example chromatograms had not been printed nor were there other documented evidence existing to show that the results were within
  20. 20. PHARMA UPTODAY 20 specification. Samples were no longer available to allow for any investigation on case of an out-of- specification (OOS) result or re-testing where appropriate. AUDIT FINDINGS - Warning letters Apotex Pharmachem India Pvt Ltd. (WL: 320-14-11): During our January 27, 2014 through January 31, 2014 inspection of your pharmaceutical manufacturing facility, Apotex Pharmachem India Pvt. Ltd. located at Plot # 1A Bommasandra Ind. Area, 4th Phase, Jigani Link Road, Bangalore, India, investigators from the U.S. Food and Drug Administration (FDA) identified significant deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs). 1. Failure to maintain complete data derived from all laboratory tests conducted to ensure compliance with established specifications and standards. • lacked accurate raw laboratory data records • samples were retested until acceptable results were obtained • failed to include complete data on QC testing sheets. • Failing or otherwise atypical results were not included in the official laboratory control records, not reported, and not investigated. • The sample preparation raw data was discarded and not reported • Karl Fischer electronic records OOS result that was not reported 2. Failure to investigate and document out-of-specification results. • to investigate unknown peaks found during the HPLC testing for related compounds • Empower software identified instances where additional testing was performed but not properly documented in laboratory record 3. Failure to include adequate documentation during complaint investigation 4. Failure to record activities at the time they are performed. • staff used “finished product reports review data” worksheets to document critical laboratory information days after the actual testing was performed • “all tests completed but appearance not reported.” Source : http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm401451.htm Tianjin Zhongan Pharmaceutical, China (WL: 320-14-09): During our September 23-27, 2013 inspection of your pharmaceutical manufacturing facility, Tianjin Zhongan Pharmaceutical Co. Ltd., located at No. 188 Fukang Road, Xiqing District, Tianjin, China, an investigator from the U.S. Food and Drug Administration (FDA) identified significant deviations of current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs).
  21. 21. PHARMA UPTODAY 21 1. Failure to adequately complete and follow written procedures for cleaning equipment and its release for use in API manufacture, and to maintain adequate records of major equipment usage. • various levels of contamination and foreign objects inside, including what looked like the remains of a pen in one of the (b)(4). Your employees had labeled this equipment as clean • your firm’s production system did not maintain equipment logs or other documents that adequately record manufacturing operations performed on individual pieces of equipment • your production operation supervisors and Quality Unit (QU) failed to detect and correct these deficient cleaning practices. 2. Failure to conduct adequate change control to evaluate all changes that could affect the production and control of intermediates or APIs. • failed to identify, document, evaluate, and approve several changes in production • failed to conduct a change control investigation or document the significant changes. 3. Failure to adequately review and investigate product deviations. • The samples collected of the residues were insufficient to allow for an adequate investigation. • You did not initiate an investigation prior to the investigator’s observation. • You conducted no further testing, and disposed of the sample after the HPLC analysis. Other Observations: • you did not adequately control your Certificates of Analysis (COAs). • inadequate qualification of critical production equipment is also a concern • you did not maintain current technical drawings of any (b)(4), or the (b)(4) production equipment used in manufacturing of (b)(4), and (b)(4) APIs. • You should ensure that the contact surfaces of your production equipment are not reactive, additive, or absorptive so as to prevent impact on the quality of your products beyond appropriate limits. Source : http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm400853.htm Lee and Company (Ref: 2014-DAL-WL-08): Between February 19, 2013 and February 21, 2013, U.S. Food and Drug Administration (FDA) investigators conducted an inspection of your facility, Sunnymede Pharmacy, Inc., dba Lee and Company and Lee Pharmacy, located at 4300 Grand Ave, Fort Smith, AR 72904-7028. During the inspection, investigators noted that you were not receiving valid prescriptions for individually-identified patients for a portion of the drug products you were producing. In addition, the investigators observed serious deficiencies in your practices for producing sterile drug products, which put patients at risk. 1. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)). 2. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).
  22. 22. PHARMA UPTODAY 22 3. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)). Source : http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm400665.htm Warning letter of ID Biomedical Corp., a subsidary of GSK Biologicals (CBER-14-03): The Food and Drug Administration (FDA) conducted an inspection of ID Biomedical Corporation of Quebec d/b/a GlaxoSmithKline Biologicals (GSK), located at 2323 du Parc Technologique Blvd, Quebec, Canada G1P4R8, from March 31, to April 9, 2014. During the inspection, FDA investigators documented deviations from current good manufacturing practice (CGMP) requirements in the manufacture of your licensed biological drug product Flulavaland its intermediates. Significant deviations observed during the inspections include, but were not limited to, the following: 1) You failed to assure that appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, are established and followed. Such procedures include validation of all aseptic and sterilization processes [21 CFR 211.113(b)]. 2) Controls for the purified water system at your facility are inadequate to prevent bioburden and endotoxin excursions. 3) Manufacturing controls in place for both the (b)(4) containing and the (b)(4) manufacturing processes are inadequate to control bioburden and endotoxin. Throughout 2013-2014 the process continued to generate Out of Specification (OOS) results for bioburden and endotoxin even after several corrective and preventive actions (CAPAs) were implemented. 4) From 2012 to 2014, viral inactivation of several monovalent lots could not be confirmed. Your explanation was that the observed microbial contamination caused high mortality of the test eggs before the (b)(4) test could be completed. These lots were rejected. 5) Your investigation into the repeated bioburden excursions associated with (b)(4) is inadequate. Source : http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm401719.htm Warning letter of Pharmacy Creations, NJ From August 5, 2013 to August 19, 2013, U.S. Food and Drug Administration (FDA) investigators conducted aninspection of your facility, Pharmacy Creations, located at 540 Route 10 West, Randolph, NJ 07869. FDA investigators also noted CGMP violations at your facility, causing the drug products for which you have not obtained valid prescriptions for individually-identified patients to be adulterated under section 501(a)(2)(B) of the FDCA [21 U.S.C. § 351(a)(2)(B)]. The violations include, for example:
  23. 23. PHARMA UPTODAY 23 1. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and also failed to use results of such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)). 2. Your firm failed to establish adequate written procedures for production and process control designed toassure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)). 3. Your firm failed to establish an adequate system for monitoring environmental conditions in asepticprocessing areas (21 CFR 211.42(c)(10)(iv)). 4. Your firm failed to establish and follow appropriate written procedures that are designed to preventmicrobiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)). 5. Your firm failed to clean and, where indicated by the nature of the drug, sterilize and process container closures to remove pyrogenic properties to assure they are suitable for their intended use (21 CFR 211.94(c)). 6. Your firm failed to test samples of each component for conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(2)) and your firm failed to subject each lotof a component that is liable to microbiological contamination that is objectionable in view of its intended use to microbiological tests before use (21 CFR 211.84(d)(6)). 7. Your firm did not conduct, for each batch of drug product purporting to be sterile and/or pyrogen-free, appropriate laboratory testing to determine whether each batch was sterile or pyrogen-free (21 CFR 211.167(a)). 8. Your firm did not have, for each batch of drug product, appropriate laboratory determination ofsatisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)). Source : http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm402773.htm AUDIT FINDINGS - EMA Non Compliance Reports MOORFIELDS PHARMACEUTICALS, United Kingdom: • Serious deficiencies related to sterility assurance, sterilisation processes and the Pharmaceutical Quality System have been identified at Moorfields Pharmaceuticals. Concerns implicate all aspects of aseptically prepared and terminally sterilised products. • Failures and non-compliances were identified with the approach to qualification and the routine controls of sterilisation.
  24. 24. PHARMA UPTODAY 24 • Poor aseptic practices were noted with manufacturing processes. Grade A HEPA filter integrity failures have been noted for some areas. • Microbiological environmental monitoring and media simulation programmes were deficient. Media simulation failures have been identified. • Serious deficiencies were noted with the Pharmaceutical Quality System. • Company Corrective and Preventative actions and remediation, to date, have failed to adequately address all deficiencies and non-compliances. • Serious deficiencies related to sterility assurance, sterilisation processes and the Pharmaceutical Quality System have been identified at Moorfields Pharmaceuticals. • Concerns implicate all aspects of aseptically prepared and terminally sterilised products. • Failures and non-compliances were identified with the approach to qualification and the routine controls of sterilisation. • Poor aseptic practices were noted with manufacturing processes. • Grade A HEPA filter integrity failures have been noted for some areas. • Microbiological environmental monitoring and media simulation programmes were deficient. • Media simulation failures have been identified. Serious deficiencies were noted with the Pharmaceutical Quality System. • Company Corrective and Preventative actions and remediation, to date, have failed to adequately address all deficiencies and non-compliances. • There is currently no evidence of non-sterile product on the market. • Most unauthorised medicinal products are small volume short shelf life, and not subject to sterility testing. • A supervisory risk assessment has been circulated via rapid alert. Non Compliance Report of SIMS, Italy by Italian Medicines Agency: • The inspection, unannounced, was performed by AIFA in collaboration with Italian police authorities and Italian custom authorities; three critical deficiencies and seven major deficiencies were found. CRITICAL DEFICIENCIES: • The presence of two unauthorized, not-GMP storage areas (declared as office area) in building 1 illegally used for storage of imported materials from China, expired API, production tails and for which the company has not provided an inventory list related to origin, status and destination of each material; an unauthorized, not-GMP repackaging station with craft dust extraction system was found in the same premises. The company has provided the inspection team contradictory information about the ownership of the premises and of the materials, initially attributing them to SIMS Trading and following to SIMS srl. • Mismatch between print inventory of "intensive warehouse" and physical stock of materials. • Use of above described unauthorized area for the distribution and repackaging of the batch of lidocaine 170686; the inspection team points out in the report that the conditions for such local do not ensure the absence of contamination by other products. The remaining deviations, all classified as "major", showed: • Serious deficiencies in filling in of production logbooks and management of the production documentation in general (devv. 1, 2, 5)
  25. 25. PHARMA UPTODAY 25 • Serious lack of hygiene in the management and maintenance of equipment and production areas (devv. 3, 4) • Serious deficiencies in the management of materials (dev. 6) • Serious deficiencies in the documentation coherence (dev. 7) Non Compliance Report of WOCKHARDT LIMITED, India: 1. A critical deficiency was cited with regards to testing of finished product and stability testing in the QC analytical laboratory. The deficiency related to data integrity, deleted electronic files with no explanantion, the running of “trial testing” prior to perfoming system suitability and the formal testing and a loss of control of reconciliation of samples such as those used for additional testing could not be traced. 2. 4 major deficiencies were cited , relating to storage, general manufacturing practices, the performance of tablet coating and qualification and validation of equipment and products. • Issues seen, included temporary storages areas that had been created immediately prior to the inspection and were not visible on the site map. Storage areas did not have adequate temperature control or monitoring and did not protect stored items from contamination from the area or the environment. • Production practices included non contemporaneous record keeping, using equipment, such as balances, that had not been correctly set up, failure to record all critical data, failure to raise deviations for incidents that may impact product quality. • Qualifications were not robust and failed to ensure that all critical elements of equipment and processes were appropriately qualified. • The major deficiency for qualifiication and validation was cited as a separate deficiency as a number of issues were seen that indicated validation may not be performed consistently and therefore could relate to some of the product testing issues such as dissolution identified as part of the critical deficiency. Non-Compliance Report of Yung Shin Pharmaceutical Ind Co Ltd, Taiwan • There was a lack of GMP control of moist heat sterilisation processes, including porous cycle design, control and validation and sterilisation-in-place of pipework and vessels. The Statement of Non-Compliance is specific to these aspects of the inspection only. • A re-inspection will be required to verify implementation of appropriate proposed actions by the company prior to issuance of a GMP certificate. Source : http://eudragmdp.ema.europa.eu/inspections/gmpc/searchGMPNonCompliance.do;jsessionid=hIn381uxOTysK PYWsir4z8OwHtK2cn- 2DPFfMy9MKRHzSxnTjTkz!2063650256?ctrl=searchGMPNCResultControlList&action=Drilldown&param=24094
  26. 26. PHARMA UPTODAY 26 Celebrating Successful completion of one year Happy anniversary… Top Pharma Uptoday modules posted last year: 1. Good Manufacturing Practices (GMP) – (Preferably on Monday) Completed more than 50 episodes & still continuing 2. Article of the Week (Preferably on Tuesday) 3. Webinar / Video / Presentation of the Week (Preferably on Wednesday) 4. 483’s of the Week (Preferably on Thursday) 5. Regulation of the Week (Preferably on Friday) 6. Drug Category (Preferably on Saturday) Completed more than 34 episodes & still continuing 7. Warning letters, 483’s, WHO-NoC, EU Non-Compliance Reports 8. Dissolution Module (10 episodes) 9. Stability (11 episodes) 10. Quality Tools (11 episodes) To get the modules, write a mail to us on “pharmauptoday@gmail.com” Few Pharma Uptoday topics can be accessed from our website https://sites.google.com/site/pharmauptoday/ To subscribe free online Newsletter write a mail to pharmauptoday@gmail.com with subject “Add mail”.
  27. 27. PHARMA UPTODAY 27 Regulations of the Month Subpart I--Laboratory Controls § 211.165 Testing and release for distribution. (e) The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with 211.194(a)(2). (f) Drug products failing to meet established standards or specifications and any other relevant quality control criteria shall be rejected. Reprocessing may be performed. Prior to acceptance and use, reprocessed material must meet appropriate standards, specifications, and any other relevant critieria. § 211.166 Stability testing. (a) There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include: (1) Sample size and test intervals based on statistical criteria for each attribute examined to assure valid estimates of stability; (2) Storage conditions for samples retained for testing; (3) Reliable, meaningful, and specific test methods; (4) Testing of the drug product in the same container-closure system as that in which the drug product is marketed; (5) Testing of drug products for reconstitution at the time of dispensing (as directed in the labeling) as well as after they are reconstituted. (b) An adequate number of batches of each drug product shall be tested to determine an appropriate expiration date and a record of such data shall be maintained. Accelerated studies, combined with basic stability information on the components, drug products, and container-closure system, may be used to support tentative expiration dates provided full shelf life studies are not available and are being conducted. Where data from accelerated studies are used to project a tentative expiration date that is beyond a date supported by actual shelf life studies, there must be stability studies conducted, including drug product testing at appropriate intervals, until the tentative expiration date is verified or the appropriate expiration date determined.

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