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Pharma Uptoday Monthly Magazine Volume 5, Issue Aug 2014

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To recap the previous month's pharma highlights to Pharma Uptoday members, Monthly magazine Volume 5 has been released with

News Uptoday

New Guidance

Audit Findings

483 Observations

- 483 of Downing Labs

- 483 of Impax Laboratories

FDA Recall letter observations

- Unique Pharmaceuticals Ltd

Warning Letters

- Pharmacy Creations, NJ

- Trifarma S.p.A., Italy

- Zhejiang Jiuzhou Pharmaceutical Co., China

EMA Non-Compliance Reports

- WOCKHARDT LIMITED, India

- SIMS Società Italiana Medicinali Scandicci srl, Italy

- SCM PHARMA LIMITED, UK

Regulations of the Month

§ 211.167 Special testing requirements

§ 211.170 Reserve Samples

§ 211.176 Penicillin contamination

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Pharma Uptoday Monthly Magazine Volume 5, Issue Aug 2014

  1. 1. VOLUME: 5 - ISSUE: AUG 2014 | PHARMA UPTODAY For feedback, suggestions & queries write to us on “pharmauptoday@gmail.com”
  2. 2. PHARMA UPTODAY 2 Inside This Issue 3 News Uptoday 15 New Guidance 21 Audit Findings 483 Observations - 483 of Downing Labs - 483 of Impax Laboratories FDA Recall letter observations - Unique Pharmaceuticals Ltd Warning Letters - Pharmacy Creations, NJ - Trifarma S.p.A., Italy - Zhejiang Jiuzhou Pharmaceutical Co., China EMA Non-Compliance Reports - WOCKHARDT LIMITED, India - SIMS Società Italiana Medicinali Scandicci srl, Italy - SCM PHARMA LIMITED, UK 27 Regulations of the Month § 211.167 Special testing requirements § 211.170 Reserve Samples § 211.176 Penicillin contamination
  3. 3. PHARMA UPTODAY 3 News Uptoday 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. 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
  4. 4. PHARMA UPTODAY 4 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 The complete version of Summary of fees and charges at 1 July 2014 published by TGA can be accessed from the 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: • 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
  5. 5. PHARMA UPTODAY 5 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 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.justice.go v/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.
  6. 6. PHARMA UPTODAY 6 "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. Wockhardt faces drug alert in UK Drug regulator in the United Kingdom (UK), Medicines and Healthcare Products Regulatory Agency (MHRA), has raised a class 4 alert against drug maker Wockhardt's amoxicillin sodium powder, used in injection to treat certain type of bacterial infection in children. The alert cautions medical practitioners from prescribing or using the drug in infants as the company has received reports of "extravasation and injection site reactions" in neonates and infants (below 1 year old). "As a precaution Wockhardt UK Ltd are asking all healthcare professionals treating neonates and infants not to use Wockhardt's Amoxicillin Sodium Powder for Solution for injection (all batches) in such patients until further notice," MHRA said in a drug alert issued earlier this week. When contacted, a Wockhardt spokesperson declined to comment. A class 4 alert is least critical in nature and is issued mainly as a precaution. The regulator has also clarified that currently there is no evidence to suggest that Wockhardt's product is defective. MHRA is also working along with the company to ensure the reports suggesting deviations are investigated at the earliest, the regulator said. Last month, Wockhardt had recalled over 8,000 bottles of anti-hypertension drug Metoprolol Succinate extended- release tablets in the US market following failure of a dissolution test. Industry analysts said the impact of the latest alert in UK may not be very huge on the financials of the company since the classification of the alert is only precautionary in nature and only the batches of the product used in children are impacted. The alert includes three different dosage size of Amoxicillin Sodium - 250 mg, 500 mg and 1gm. However, given that Wockhardt is already facing regulatory hiccups in the US and UK markets, similar problems for a long time have potential to increase stress on its revenues, analysts said. Some of the key facilities of the company in India are barred by the US Food and Drug Administration from supplying medicines to the American market, whereas some are also under scanner of MHRA as it had identified some poor manufacturing practices at some sites. Drug Alert: Manufacturers and importers are obliged to report to the MHRA any quality defect in a medicinal product which could result in a recall or restriction on supply. Other users and distributors of medicinal products are encouraged to do this. Where a defect is considered to be a risk to public health, the marketing authorisation holder withdraws the affected product from use and the MHRA issues a 'drug alert' letter. This alert is classified from 1 to 4 depending upon the risk presented to the public health by the defective product. Class 1 is the most critical, for example serious mislabelling, microbial contamination or incorrect ingredients, and requires immediate recall; Class 4 is the least critical and advises 'caution in use'.
  7. 7. PHARMA UPTODAY 7 India’s CDSCO Sets up Whistleblower Reward Scheme India’s Central Drugs Standard Control Organisation (CDSCO) has set up a scheme for providing monetary rewards to informers who provide specific information leading to the seizures of spurious, adulterated, misbranded and not-of-standard-quality drugs, cosmetics and medical devices. This reward scheme will be applicable to both the informers and CDSCO officers involved. The plan calls for rewards of up to 20% of the value of the products seized, to a maximum of around $41,500 for informants and around $8,300 for CDSCO officials. The reward is to be provided only when the spurious, adulterated and misbranded products are actually seized by CDSCO. In order to ensure the continued cooperation of informants, 25% of the amount is to be awarded at the time of filing of the case in court, another 25% upon a favorable disposition of the case at the first trial level, and the remaining 50% upon final disposition in favor of the government with no appeal pending. The reward scheme will be overseen by the Drug Controller General of India (DCGI), along with other officials. The eligibility of informants and the amount of rewards will be decided by a Committee chaired by the Director General for Health Services, and including representatives from CDSCO, the Customs Department, the Ministry of Health and Family Welfare and social groups/NGOs. Insufficient failure investigations, supplier qualification, stability testing - the most common GMP violations in the FDA warning letters The analysis of the warning letters issued in the last fiscal year shows no surprise at a first glance: as in recent years the FDA detected an insufficient investigation of unexplained discrepancies and deviations from defined standards and specifications in their inspections. The corresponding paragraph 21 CFR 211.192 requires that the drug maker clarifies the reason for the deviation, takes corrective actions and also creates a complete documentation. In the last 5-year period on average annually about 22 companies received a warning letter listing this GMP deficiency. This fact shows that many quality assurance departments' understanding of deviations handling, failure investigations and corrective actions is frequently fragmentary. Quite interesting is the detailed study of the warning letters referring to GMP violations with regard to 211.192. These warning letters take into account the drugs' dosage forms. In particular manufacturers of oral dosage forms were addressees of warning letters containing citations with regard to 211.192, followed by parenteral drugs manufacturers, companies in the area of blood/blood products and manufacturers of topical drugs. The respective scenarios are quite different. However, main shortcoming is always the inadequate education and documentation in each incident. A rather unexpected finding in the lineup of the most common GMP violations is the high number of citations with regard to 21 CFR 211.84 "Testing and approval or rejection of components, drug product containers, and closures". This quote appears so frequently as never before: 16 out of the 32 companies that received a warning letter in the fiscal year 2013 for violations of part 211 had not implemented the provisions of paragraph 211.84 as expected by the FDA investigators. Interestingly, in this case most of these companies (12 of the 16) are manufacturers of topical products (ointments, creams, etc.). The formulations in the warning letters in this regard are very similar (in some cases identical) and are usually limited to the following standard wording: "Your firm has not established the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals" or "Your firm failed to withhold from use each lot of components, drug product containers, and closures until the lot had been sampled, tested, or exampled, as appropriate, and released for use by the quality control unit."
  8. 8. PHARMA UPTODAY 8 Under the addressees of warning letters with quotations in the area of quality control - 21 CFR 211.166 "Stability Testing" and21 CFR 211.160 "General Requirements" - there are also many of the companies that were already criticised due to non-compliances with regard to 211.84. This is not surprising as the thematic connection of all three paragraphs has a reference to the function of quality control. These two paragraphs 211.166 and 211.160 - just as 211.192 - have been in the top ten of GMP deficiencies for many fiscal years. Main shortcoming relating to 211.166 is the lack of a written stability test programme. Therefore, the following sentence can be read in almost all warning letters: "Your firm does not have an adequate written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates." Information on infringements of 211.160 are more differentiated. Partly some interesting scenarios are described, as, for instance, "inappropriate visual particle inspection" or "switched off audit trail function in the chromatography system". Here too Topika makers make the majority of addressees - even though not as clear as in the previous paragraphs of part 211. Main shortcoming in the implementation of the guidelines in 211.160 is the lack of scientifically sound and appropriate specifications, standards, test plans and test methods for products, intermediates, components etc. The analysis of the warning letters of last fiscal year has shown that the FDA increasingly focuses on the subject "supplier qualification" and in this context on critically questioning analysis results and certificates of the suppliers. A detailed examination of the warning letters of the current fiscal year will show whether this trend further continues. Source: http://www.gmp-compliance.org/enews_4390_Insufficient-failure-investigations%2C-supplier- qualification%2C-stability-testing---the-most-common-GMP-violations-in-the-FDA-warning-letters_rss.html Ipca Laboratories has halted shipments to the US of active pharmaceutical ingredients (APIs) made from a facility in India following a US FDA inspection. In a letter to the Bombay Stock Exchange , the company announced today its Ratlam plant in the Madhya Pradesh region of India received a form 483 citing an undisclosed number of observations from a recent inspection by the US Food and Drug Administration (FDA). “Consequent to this, the Company has voluntarily decided to temporarily suspend API shipments from this manufacturing facility for the US markets till [sic] this issue is addressed,” the letter signed by Joint Managing Director Ajit Jain said. The decision will affect the firm’s formulation business as APIs made at the plant – which according to Ipca’s annual report was expanded in the 2013/4 financial year – are used at Ipca’s sites in Piparia and Indore (both in India) for formulating products for the US market. Share prices for the firm dropped 13% across the course of Thursday following the letter’s submission to the stock exchange. Jain’s letter said the firm “is fully committed in resolving this issue at the earliest.” The API business accounts for almost 25% of Ipca’s revenues, according to its website which lists 57 commercial substances with Drug Master File (DMF) available in the US manufactured from its six Indian sites.
  9. 9. PHARMA UPTODAY 9 Every fifth FDA Warning Letter includes deficiencies regarding Equipment The considered period from 2012 until the first quarter of 2014 pertains to both companies in and outside of the United States. None of the 19 mentioned warning letters is solely due to deficiencies regarding equipment. However, the big picture shows the lack of understanding of FDA requirements relative to used production equipment. In almost every case there are references to violations against requirements defined in 21 CFR 211.67 (equipment cleaning and maintenance), such as the absence of a maintenance system or a maintenance system that doesn't fulfill the requirements. In one case scratches and rust in production boilers were found. In another case the authority found obvious defects with regard to the condition of the equipment, and in addition objected to the complete lack of plans for maintenance and maintenance/cleaning of the production building. The routine calibration was found to be insufficient in another case, and records of calibration work carried out were even missing completely. The qualification of production equipment can be found on the list of shortcomings as well. In one case, for example, the missing accuracy check of a tablet test station (hardness, weight) depending on the different possible speed settings as part of the PQ was criticized. Also, the ejection of tablets in relation to the tablet press' different velocities was insufficiently considered in the PQ. In two warning letters issued to companies in China and Taiwan, the qualification of the production equipment was found to be completely absent. In most cases, though, the warning letters are the response to an insufficiently comprehensive catalogue of measures following the findings in previous inspections. For example, in a case the required calibrations were found to be missing. But the company's reply lacked information regarding the evaluation of the batches on the market that had been manufactured with non-calibrated equipment. In another case - affected was the maintenance and cleaning of a filling line - the evaluation was supposed to be extended to other products which had been manufactured with the faulted system. It is also expected that the newly created maintenance and cleaning plans plus a statement relative to their effectiveness is submitted as well. Somewhat abstruse is the case of another company which had already been noted with regard to the missing or deficient maintenance and cleaning of their facilities in 2001, 2003 and in 2011. In a new FDA inspection in 2012 the appropriate SOPs were still found in draft status. European Pharmacopoeia plans revisions of elemental impurities guideline As the International Conference on Harmonisation (ICH) signs off on a new tripartite guideline related to elemental impurities, the European Pharmacopoeia Commission will revise its texts to ensure consistency. Following its last meeting in early June 2014, the ICH Steering Committee announced the plan to move their guideline for elemental impurities, known as ICH Q3D , to Stage 4 in September 2014. As the sign off of this new tripartite guideline approaches, a strategy for the revision of the texts concerned has been drawn up by the European Pharmacopoeia Commission to ensure that a consistent approach between the licensing authorities and the commission continues to be applied. The ICH unveiled the guideline for comment in August, noting that limiting metal impurities is contingent on evaluating toxicity data, establishing a Permitted Daily Exposure (PDE) rate for the elements of concern, and ensuring that rate isn’t met by any of a treatment’s ingredients. The European Pharmacopoeia Commission endorsed the proposed revision by the ICH of the current “Heavy metals chapters” and decided as a first step to revise a chapter on metal catalyst or reagent residues to replace its content by the ICH Q3D guideline as soon as it has moved to Stage 5 in the European Union. The decision to
  10. 10. PHARMA UPTODAY 10 replace the EMA guideline on the specification limits for residues of metal catalysts or metal reagents by the ICH Q3D guideline is under the remit of the Committee for Medicinal Products for Human Use (CHMP). Currently, the EMA Guideline on the specification limits for residues of metal catalysts or metal reagents is located in chapter 5.20: “Metal catalyst or metal reagent residue,” which is applicable to new drugs to be marketed in Europe. In line with a decision from April 2012, the European Pharmacopoeia intends to introduce a cross-reference to this revised chapter in two general monographs: Substances for pharmaceutical use (2034) and Pharmaceutical preparations (2619) at a later stage. The cross-references would make the requirements of the ICH Q3D Guideline legally binding. The exact timing of this step will depend on the implementation decisions of other European regulation bodies, mainly the CHMP. Monograph Changes In addition, it is planned to delete cross-references to the wet chemical tests for “heavy metals” from all individual monographs (except for monographs on products for veterinary use only). The list of all impacted monographs will be published in Pharmeuropa, in January 2015. The European Pharmacopoeia says it foresees publishing revised individual monographs in the 9th edition with an implementation date of January 2017. From then on, the choice of an appropriate analytical strategy will be left to the user, in line with the ICH Q3D guideline. Chapter 2.4.20, currently entitled “Determination of metal catalyst and metal reagent residues,” which focuses on sample preparation and method suitability, will provide additional guidance. Together with other general chapters related to elemental impurities analysis, the new guideline will be thoroughly reviewed to align them, if necessary, with the latest requirements from the ICH Q3D guideline. Additionally, the Pharmacopoeial Discussion Group (PDG) decided at its last meeting in June 2014 to start the discussions on the harmonisation of their respective chapters on elemental impurities. The changes come as IPEC (International Pharmaceutical Excipient Council) Americas in April asked its member companies to compile information on elemental impurities. Meanwhile, the ICH M7 Guideline on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk is now entering the implementation period. Focus on enforcement review of pharmaceutical manufacturing and production sector The Department of Business, Innovation & Skills (BIS) has completed the Focus on Enforcement (FoE) review of the pharmaceutical sector and have reported on how well rules governing the sector are applied, delivered and enforced. The GMDP Inspectorate has agreed to: • ask industry if there is more we can do to improve the accuracy of information we send to companies applying for manufacturing wholesale dealer’s licence applications and variations by providing specific examples of errors or inaccuracies (in response to finding 1B)
  11. 11. PHARMA UPTODAY 11 • ask industry if there is more we can do to improve the time taken to process notifications to import unlicensed medicines by providing examples of the actual time taken to receive notification letters (in response to finding 3) • communicate the existing escalation process available for challenging inspector decisions (in response to finding 6). If you want to challenge an inspection decision, the first opportunity would be to raise any concerns with the inspector at the time either during the inspection or at the closing meeting. The GMDP Inspectorate structure is published on the MHRA website and so any unresolved concerns can be escalated to the relevant GMDP Operations Manager. Any general concerns about GMP interpretation can be raised through the GMDP consultative committee, as a two-way exchange and discussion of inspection experience and explanation of GMP expectations. Source: http://www.mhra.gov.uk/Howweregulate/Medicines/Inspectionandstandards/GoodManufacturingPractice/N ews/CON437745 FDA publishes Listing of Authorized Generics This list of authorized generic drugs (AGs) was created from a manual review of FDA’s database of annual reports submitted to the FDA since January 1, 1999 by sponsors of new drug applications (NDAs). Because the annual reports seldom indicate the date an AG initially entered the market, the column headed “Date Authorized Generic Entered Market” reflects the period covered by the annual report in which the AG was first reported. Subsequent marketing dates by the same firm or other firms are not included in this listing. As noted, in many cases FDA does not have information on whether the AG is still marketed and, if not still marketed, the date marketing ceased. Although attempts have been made to ensure that this list is as accurate as possible, given the volume of data reviewed and the possibility of database limitations or errors, users of this list are cautioned to independently verify the information on the list. We welcome comments on and suggested changes (e.g., additions and deletions) to the list, but the list may include only information that is included in an annual report. The listing can be accessed from the source:http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm126391.htm. Management reshuffle at Ranbaxy ahead of Sun Pharma's takeover In a quiet shake-up, Ranbaxy Labs has elevated Arno Gessner to the position of head of global quality, in place of Dale Adkisson who has stepped down, and appointed Alexander Gebauer as its new head of global research and development, people aware of the development told. The executive committee-level changes come within months of rival drugmaker Sun Pharma agreeing to acquire Ranbaxy from its Japanese parent, Daiichi Sankyo, in a $4-billion deal. A Ranbaxy spokesperson refused comment. Adkisson, a Daiichi veteran, was Ranbaxy's global quality and compliance head. He had joined Ranbaxy in early 2010 when Ranbaxy was dogged by regulatory setbacks in the US. During his tenure, the company signed the consent decree with US Food and Drug Administration (FDA), promising to improve manufacturing practices, and also launched the first generic of the blockbuster drug Lipitor. Subsequently, however, Ranbaxy's regulatory crisis deepened in the US and two of its India based plants were banned from exporting to the US. Gessner, who replaces him, was regional director of quality in charge of Europe, Africa and East Europe. Besides inducting Gessner in the executive committee, Ranbaxy has also appointed Gebauer as its new head of global R&D. Gebauer was formerly the R&D chief of Merz Pharma, a German specialty research firm, and has worked with French innovator drug firm Sanofi Aventis. He steps into the role of Sudershan Arora, which had fallen vacant after he retired as the president of R&D last year.
  12. 12. PHARMA UPTODAY 12 At least two people familiar with the changes told ET that Rajiv Gulati, Ranbaxy's president of global pharma business, another executive committee member, has also put in his papers. However, it is not clear whether his resignation has been accepted. "He has been on a long leave for personal reasons, during which his work is being looked after by Ranjan Chakravarti as additional charge," one of the persons said. The Ranbaxy spokesperson did not confirm this either. Chakravarti serves as the head of transformation and business consulting and, more importantly, also heads the integration committee both Ranbaxy and Sun have formed to ease out the process of merger. Ever since the takeover was announced in April, the rumour mill has been swirling about possible senior management-level changes at Ranbaxy. "People at Ranbaxy have been anxious about their jobs, particularly because many of them earn much higher salaries when compared to industry standards, including that of Sun" a headhunter told. FDA Announces Fiscal Year 2015 Generic Drug User Fee Rates U.S. Food and Drug Administration (FDA) published the fiscal year 2015 generic drug user fee rates as required under the Food Drug and Cosmetic Act as amended by the Generic Drug User Fee Amendments of 2012 (GDUFA). This announcement includes the rate for the abbreviated new drug application (ANDA), prior approval supplement to an approved ANDA (PAS), drug master file (DMF), active pharmaceutical ingredient (API) facilities, and finished dosage form (FDF) facilities user fees. GDUFA authorizes FDA to assess and collect user fees for certain applications and supplements for human generic drug products, on certain generic FDF and API facilities, and on type II active pharmaceutical ingredient DMFs to be made available for reference for generic applications. These fees are effective on October 1, 2014, and will remain in effect through September 30, 2015. FDA publishes Manual of Policies and Procedures (MAPP) on "Drug Development Tool Qualification Programs" This MAPP describes general policies, responsibilities, and procedures for drug development tool (DDT) qualification programs at the Center for Drug Evaluation and Research (CDER). Currently, DDT qualification programs exist for biomarkers, clinical outcome assessments (COAs), and animal models for drug development under the animal rule. These programs are led by the Office of Translational Sciences (OTS), Office of New Drugs (OND), and Office of Counter-Terrorism and Emergency Coordination (OCTEC), respectively. This MAPP is intended to serve as a companion reference to the guidance for industry and FDA staff Qualification Process for Drug Development Tools (DDT qualification guidance). FDA publishes Manual of Policies and Procedures (MAPP) on "Good Review Practice: Management of Breakthrough Therapy-Designated Drugs and Biologics" This MAPP describes actions taken in the Center for Drug Evaluation and Research (CDER) “to expedite the development and review of a breakthrough therapy . . . ” consistent with requirements described in section 902 of the Food and Drug Administration Safety and Innovation Act (FDASIA). It outlines CDER actions from the time a breakthrough therapy designation has been granted until a marketing application has been submitted. This MAPP describes the policy, roles and responsibilities of CDER review staff, CDER-sponsor interactions and communications, and review timelines for the management of breakthrough therapy-designated drugs. These descriptions are intended to facilitate and expedite development and review of investigational new drug application (IND) submissions for these drugs.
  13. 13. PHARMA UPTODAY 13 Guidance: A guidance refers to any written communication that explains an Agency or Center policy or procedure. The term guidance generally refers to guidance for regulated entities (e.g., the pharmaceutical industry). In some instances, CDER has developed reviewer guidance or guidance for industry and reviewers. Guidance documents do not include (1) FDA reports; (2) general information provided to consumers; (3) documents relating solely to internal FDA procedures (e.g., where there is no external interaction); (4) speeches, journal articles, editorials, or media interviews; (5) warning letters; (6) other communications or actions taken by individuals at the FDA directed to individual persons or firms. MAPP (Manual of Policies and Procedures): Agency and CDER policy directed toward the performance of the daily activities of Center personnel are called MAPPs and are kept in the CDER Manual of Policies & Procedures, from which the name MAPP is taken. A MAPP may be issued by any CDER administrative level (center, office, division, staff, branch, or section) and can apply to Center administration and management as well as program activities. Employees are responsible for staying up to date on the directives outlined in Center MAPPs. Guideline, Guidance Memoranda, Points to Consider: These terms were previously used to refer to guidance documents. This nomenclature is no longer being used. Regulation, Rule: Both terms refer to legally binding and enforceable requirements that are promulgated through notice and comment rulemaking.
  14. 14. category Non Compliance Reports Basics Quality tools Webinars VIdeos PHARMA UPTODAY News Articles Guideline Regulation Drug category VIdeos PHARMA UPTODAY 14 Warning letters 483's GMP Presentation
  15. 15. PHARMA UPTODAY 15 New Guidance 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/UCM403496 .pdf US FDA published Guidance for Industry : Neglected Tropical Diseases of Developing World: Developing Drugs for Treatment or prevention The purpose of this guidance is to assist sponsors in the development of drugs for the treatment or prevention of neglected tropical diseases (NTDs) of the developing world. Specifically, this guidance addresses the Food and Drug Administration’s (FDA’s) current thinking regarding the overall drug development program for the treatment or prevention of NTDs, as defined in section 524(a)(3) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), including clinical trial designs and internal review standards to support approval of drugs. Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM269221 .pdf Guidance on Biopharmaceutic studies has been updated by Australian Regulatory Guidelines for Prescription Medicines (ARGPM). This guidance is to assist sponsors of prescription medicines to prepare applications to: • register new prescription medicines on the ARTG • vary the registration of a prescription medicine on the ARTG. This guidance covers: • all matters relating to bioavailability and/or bioequivalence aspects of prescription medicines containing active substances that are synthetic chemical entities • active substances that are: o antibiotics o short-chain synthetic polypeptides • some hormones (steroid hormones and synthetic peptides of usually less than 32 amino acids-some exceptions may apply).
  16. 16. PHARMA UPTODAY 16 This guidance does not cover: • Prescription medicines that are defined as biological medicines. • Matters relating to other pharmacokinetic studies. Contents 15.1 Adopted European guidelines for biopharmaceutic studies 15.2 Comparative dissolution profiles for biopharmaceutic studies 15.3 Medicines that do not require biopharmaceutic data 15.4 Medicines that require biopharmaceutic data 15.5 Validation and quality control of assay procedures used in biopharmaceutic studies 15.6 Choice of the reference product for bioequivalence of generic medicines 15.7 Managing dropouts in bioequivalence studies 15.8 Where to include biopharmaceutic data 15.9 Justification for not submitting biopharmaceutic data Source : http://www.tga.gov.au/industry/pm-argpm-guidance-15-00.htm#.U72PkfmSwiw Guidance for Industry: ANDA Submissions — Amendments and Easily Correctable Deficiencies Under GDUFA This guidance is intended to assist applicants preparing to submit to the Food and Drug Administration (FDA) amendments to abbreviated new drug applications (ANDAs) or prior approval supplements (PASs) under section 505(j) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act), by explaining how the performance metric goals established as part of the Generic Drug User Fee Amendments of 2012 (GDUFA) apply to these submissions. Specifically, this guidance does the following: • Describes the Tier system for the different types of amendments • Explains how different types of amendments may affect the application’s original review dates • Explains FDA’s performance metric goals based on the different amendment Tiers • Explains the process for submitting amendments • Describes the request for reconsideration process for FDA classification decisions Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM404440.pdf
  17. 17. PHARMA UPTODAY 17 Guidance for Industry: ANDA Submissions – Prior Approval Supplements Under GDUFA This guidance is intended to assist applicants preparing to submit to the Food and Drug Administration (FDA) prior approval supplements (PASs) and amendments to PASs for abbreviated new drug applications (ANDAs) submitted under section 505(j) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 355(j)). The guidance explains how the Generic Drug User Fee Amendments of 2012 (GDUFA) relates to PAS submissions. The guidance also describes performance metric goals outlined in the GDUFA Commitment Letter, which FDA has agreed to meet, and clarifies how FDA will handle a PAS and amendments to a PAS for an ANDA subject to the GDUFA performance metric goals. Specifically, this guidance describes how the GDUFA performance metric goals apply to: • A PAS subject to the refuse-to-receive (RTR) standards • A PAS that requires an inspection • A PAS for which an inspection is not required • An amendment to a PAS • Other PAS-related matters Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM404441.pdf Guidance for Industry: Reporting Drug Sample Information Under Section 6004 of the Affordable Care Act This guidance document is intended to assist persons reporting drug sample distribution information to FDA under section 6004 of the Patient Protection and Affordable Care Act (ACA). The guidance explains, among other things: • The statutory requirement to submit drug sample distribution information • Definitions relevant to drug sample distribution information submissions • Who submits drug sample information • What information is to be submitted • How to submit the information • When to submit the information • FDA’s compliance policies related to drug distribution information submissions Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM404473.pdf FDA publishes draft QbR - QOS Questions - Drug Substance (Chemistry) This list contains revised DRAFT Question‐based Review (QbR) questions developed using the current and previous draft questions, and utilizing internal and external comments and suggestions received. (Note: This list supersedes the list of DRAFT QbR questions posted for comment on 9/6/2012). We encourage the generics industry to provide comments to these DRAFT questions. Comments can be sent to genericdrugs@fda.hhs.gov. Please clearly state that you are commenting on the draft Chemistry QbR questions. The draft QbR – QOS questions can be accessed from the source: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Approv alApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM401139.pdf
  18. 18. PHARMA UPTODAY 18 Guidance for Industry: Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications: In section 745A(a) of the FD&C Act, Congress granted explicit authorization to FDA to implement the statutory electronic submission requirements in guidance. Accordingly, as indicated by the use of the words must or required, this document is not subject to the usual restrictions in FDA’s good guidance practice (GGP) regulations, such as the requirement that guidances not establish legally enforceable responsibilities (see 21 CFR 10.115(d); see also the 745A(a) Implementation Guidance). To comply with the GGP regulations and make sure that regulated entities and the public understand that guidance documents are nonbinding, FDA guidances ordinarily contain standard language explaining that guidance documents should be viewed only as recommendations unless specific regulatory or statutory requirements are cited. FDA is not including this standard language in this guidance document because it is not an accurate description of all of the effects of this guidance document. Insofar as this document specifies the format for electronic submissions, or provides “criteria for . . . exemptions” under section 745A(a) of the FD&C Act, it will have binding effect. Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM333969.pdf TGA publishes "Compositional Guideline for Hydroxycitrate complex" Hydroxycitrate complex is derived from the fruit rind of Garcinia quaesita Pierre or Garcinia zeylanica Roxb. It contains one or more of the three salts (calcium, potassium or sodium) of hydroxycitric acid. Varying amounts of plant material from G. quaesita or G. zeylanica may still be present in the substance depending on the manufacturing process employed, but should not exceed 10% of the final preparation. For more details browse: http://www.tga.gov.au/pdf/cm-cg-hydroxycitrate-complet-140729.pdf New General Chapter <1223.1> Validation of Alternative Methods to Antibiotic Microbial Assays Proposed in Pharmacopeial Forum A new General Chapter <1223.1> Validation of Alternative Methods to Antibiotic Microbial Assays was proposed in PF 40(4) [Jul.–Aug. 2014]. This proposed General Chapter contains guidelines to demonstrate equivalency between microbial assay procedures and chromatographic procedures. In addition to publishing in Pharmacopeial Forum, USP is providing this notice to further engage stakeholders (e.g., manufacturers, distributors, healthcare providers) to identify and discuss potential impacts of the General Chapter on the pharmaceutical industry. Microbiological assay methods are used to quantify the potency, or antimicrobial activity, of antibiotics. These microbial assays provide a direct measure of the effectiveness of the antibiotic against a reference microorganism. However, microbial assays have limited selectivity and are not appropriate for evaluating organic impurities. Also, the specific skill sets required for performing microbiological antibiotic assays, their unique equipment requirements, and their comparative complexity deter many stakeholders from using these methods. In contrast, physicochemical analytical procedures, such as high-performance liquid chromatography (HPLC), allow for simpler preparation and analysis of samples and rapid data acquisition with improved precision, accuracy, selectivity, and specificity. Alternative methods can be used effectively for both potency assignment and organic impurity testing. This proposed General Chapter presents points to consider for stakeholders who wish to use physicochemical methods such as HPLC as alternatives to the microbial assay methods described in General Chapter Antibiotics— Microbial Assays <81>. General Chapter <1223.1> was drafted by an Expert Panel consisting of individuals from industry and from regulatory agencies. The panel operated at the direction of the General Chapters—Microbiology Expert
  19. 19. PHARMA UPTODAY 19 Committee. The Monographs—Small Molecules 1 Expert Committee, which is responsible for the antibiotic monographs in USP–NF, also contributed to the development of the General Chapter. Interested parties are invited to comment on the proposal. The comment deadline is for this proposal is September 30, 2014. USP Seeks Submission of Proposals for Monograph Modernization USP has embarked on a global initiative to modernize many of our existing monographs across all compendia. Having current monographs is tantamount to our mission of providing high-quality public standards. Towards that end, we are seeking industry collaborators to assist us in the development of these monographs. Please review the attached list. It contains the names of the top 500 high priority monographs requiring modernization. USP intends to modernize these monographs as soon as possible utilizing one of two primary ways: traditional submission from a stakeholder (e.g. manufacturer of article) or USP’s internal laboratory efforts. Monographs for which USP fails to receive submissions by December 26, 2014 will be directed to our laboratory. There are two ways in which you can help: o Submit your current analytical methods o Provide sample amounts of the article for USP’s internal lab development For more information or to inform us of your participation, please contact the Standards Acquisition Department at stacq@usp.org. Download the Monograph Modernization list. Monographs and General Chapters Affected by Revision to Viscosity-Related General Chapters <911>, <912>, and <913> In accordance with section 7.05(c) of the 2010–2015 Rules and Procedures of the Council of Experts, this is to provide notice that USP and its Expert Committees, as applicable, intend to revise multiple monographs and General Chapters in response to the revision of General Chapter <911> Viscosity-Capillary Viscometer Methods, General Chapter <912> Rotational Rheometer Methods, and General Chapter <913> Rolling Ball Viscometer Method. General Chapters <911>, <912>, and <913> were proposed for comment in Pharmacopeial Forums 39(5) and 39(6) and will appear in USP 38–NF 33 with an official date of May 1, 2015. These revisions included changes to the titles of the General Chapters. USP has identified numerous monographs and General Chapters that reference General Chapters <911>, <912>, and <913> and thus require revision to modify these references. USP has conducted a careful analysis of these references and determined two potential approaches for their modification. Many of the references will be modified when the monographs and General Chapters appear in USP 38-NF 33. Others have been or will be modified through publication in Pharmacopeial Forum. Lists of the monographs and General Chapters and the mechanism by which their references to General Chapters <911>, <912>, and <913> will be modified can be found at the links <911>, <912> and <913>.
  20. 20. PHARMA UPTODAY 20 Monographs and General Chapters Affected by Omission of General Chapter <231> Heavy Metals In accordance with section 7.05(c) of the 2010–2015 Rules and Procedures of the Council of Experts, this is to provide notice that USP and its Expert Committees, as applicable, intend to revise multiple monographs and General Chapters in response to the omission of General Chapter <231> Heavy Metals. On December 27, 2013, USP announced that General Chapters <232> Elemental Impurities—Limits and <2232> Elemental Contaminants in Dietary Supplements will be made applicable to all drug products (<232>) and finished dietary supplement dosage forms (<2232>) on December 1, 2015 through General Notices 5.60.30 Elemental Impurities in USP Drug Products and Dietary Supplements. At the same time, the omission of General Chapter <231> Heavy Metals will become official. More information about these revisions can be found at the Elemental Impurities Key Issues Webpage USP has identified numerous monographs and General Chapters that reference General Chapter <231> and thus require revision to remove these references. USP has conducted a careful analysis of these references and determined two potential approaches for their deletion. Many of the references will be marked for deletion when the monographs and General Chapters appear in USP 38-NF 33. Others have been or will be proposed for deletion in Pharmacopeial Forum. A list of these monographs and General Chapters and the mechanism by which their references to General Chapter <231> will be deleted can be found here. All deletions will become official on December 1, 2015 to coincide with the omission of General Chapter <231>. For certain monographs and general chapters that currently reference General Chapter <231>, the reference to <231>, or “Heavy Metals,” will be indicated by (Official 1-Dec-2015) and will not be present in the revisions of these standards published in USP 38-NF 33 on November 1, 2014. In these cases the reference to General Chapter <231> will still be considered official between May 1, 2015 (when the USP 38-NF 33 becomes official) and December 1, 2015 (when the omission of General Chapter <231> becomes official), even though this reference does not appear. A list of the monographs that USP has identified that will be missing the “to be deleted” <231> requirement in the USP 38-NF 33 product can be found here. Please also see the Compendial Notice: New Revision Markup for Reference Changes in USP–NF for details on the revision markup used to identify the reference updates. Source: http://www.usp.org/usp-nf/notices
  21. 21. PHARMA UPTODAY 21 AUDIT FINDINGS - 483 Observations Firm Name 483 Observation PI Pharma, Inc. You did not establish and follow written procedures for the test and examinations conducted to determine whether specifications are met. Pacira Pharmaceuticals, Inc. Actual yield and percentages of theoretical yield are not determined at the conclusion of each appropriate phase of manufacturing and processing of the drug product. Alva-Amco Pharmacal Companies, Inc. Written records of investigations of a drug complaint do not include the follow- up. Lab Express, Inc. Laboratory control records do not contain all data derived from testing to ensure compliance to established specifications. Emcure Pharmaceuticals USA, Inc. An NDA Field Alert Report was not submitted within three working days of receipt of information concerning significant chemical, physical or other change or deterioration in a distributed drug product. FMC Corp. The responsibilities and procedures applicable to the Quality Assurance Unit are not fully followed. Diversified Manufacturing Corp. Laboratory controls do not include the establishment of scientifically sound and appropriate specifications, standards, sampling plans and test procedures designed to ensure that components and drug products conform to appropriate standards of identity, strength, quality and purity. Vils Pharma Coating, Inc. The quality control unit lacks responsibility for approving or rejecting drug products manufactured, processed and held under contract by another company. Dermamedics, LLC There is no quality control unit. P&L Development, LLC Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the final specifications prior to release. Genzyme, Division of Sanofi Company Written records of investigations into unexplained discrepancies and the failure of a batch or any of its components to meet specifications do not always include the conclusions and follow up. Sage Products, Inc. There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed. June Jacobs Labs, LLC Employees engaged in the manufacture and processing of a drug product lack the training required to perform their assigned functions. Sunrise Pharmaceuticals, Inc. There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed. Kutol Products Co. Written records of investigations into unexplained discrepancies and the failure of a batch or any of its components to meet specifications do not always include the conclusions and follow-up.
  22. 22. PHARMA UPTODAY 22 483 of Downing Labs – Observations: 1. There is a failure to thoroughly review 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. 2. Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established. 3. Aseptic processing areas are deficient regarding the system for monitoring environmental conditions. 4. Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic conditions. 5. Each batch of drug product purporting to be sterile and pyrogen-free is not laboratory tested to determine conformance to such requirements. 6. Equipment and utensils are not maintained at appropriate intervals to prevent malfunctions and contamination that would alter the safety, identity, strength, quality or purity of the drug product. 7. Adequate lab facilities for testing and approval or rejection of drug products are not available to the quality control unit. 8. 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. 9. Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the room to produce aseptic conditions. 10. Clothing of personnel engaged in the manufacturing of drug products is not appropriate for the duties they perform. Specifically, the goggles used by technicians in the ISO·5 clean room are not sterile and are not disinfected prior to use. 11. There is no written testing program designed to assess the stability characteristic of drug products. 12. Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the identity and strength of each active ingredient prior to release. 13. Master production and control records lack complete manufacturing and control instructions. 483 of Impax Laboratories, Taiwan – Observations 1. Equipment used in the manufacture of drug products is not appropriately validated to facilitate operations for its intended use. 2. Examination and testing of samples is not done to assure that in-process materials conforms to specification. 3. Drug products failing to meet established specifications are not rejected. 4. Not established an acceptable range of process parameters for quality attributes in process qualification/ validation of a product (tablets). 5. Failed to document information regarding the need in aberrant test results or OOS results. 6. Failed to conduct a thorough review of the failure of a batch or its components to meet any of its specifications whether or not the batch has been already distributed. 7. BMS & RMS for your facility are used to monitor & control temperature, RH & differential pressure in your prescription drug manufacturing suites and supporting areas, while you have generated data regarding action and alert events in these areas and your Quality, Production, Engineering departments did not evaluate to identify if there are any drifts and/or trends in your processing controls that should be adjusted or corrected. 8. Establishment of the reliability of the component supplier's report of analysis is deficient in test results are not appropriately validated at appropriate intervals. 9. Annual Product Review procedure - failed to include the requirement for a timely annual review of Rx drug products and did not generate annual report of complaints, recalls etc. 10. Procedures designed to prevent objectionable microorganisms in drug products not required to be sterile are not established.
  23. 23. PHARMA UPTODAY 23 AUDIT FINDINGS - FDA Recall Letter Unique Pharmaceuticals Ltd. - Observations 1. Your firm obtained failing results on sterility tests on several lots of product, and endotoxin tests on one lot of product, and you failed to adequately investigate these sterility and endotoxin failures. Your firm improperly invalidated failing results, did not conclusively identify a root cause, and did not evaluate the impact on other batches. 2. Your firm has recurring and pervasive contamination problems in your cleanrooms. 3. Poor aseptic practices were observed during production 4. The environmental monitoring conducted by your firm is inadequate 5. Investigators observed that the design of the facility is inadequate AUDIT FINDINGS - Warning letters Pharmacy Creations, NJ From August 5, 2013 to August 19, 2013, U.S. Food and Drug Administration (FDA) investigators conducted an inspection 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: 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 of satisfactory 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
  24. 24. PHARMA UPTODAY 24 Trifarma S.p.A., Italy warning letter During our January 27 – 29, 2014 inspection of your pharmaceutical manufacturing facility, Trifarma S.p.A. located at Via Pavese 2, Rozzano, Italy, an investigator 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). Warning letter citations: 1. Failure to maintain complete data derived from all testing and to ensure compliance with established specifications and standards pertaining to data retention and management. • did not retain complete raw data • failed to retain basic chromatographic information • lack of data control • review of analytical data did not include evaluating the system suitability parameters. • you do not address the backup of the injection sequence, the instrument method or audit trails 2. Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data. did not have proper controls in place to prevent the unauthorized manipulation HPLC and gas chromatograph (GC) computer software lacked active audit trail functions your firm lacked electronic raw data supporting cleaning, method and process validations 3. Failure to ensure that employees receive appropriate and documented training on the particular operations that the employee performs. did not document any training of production employees on the production operations they perform unaware that they should follow the SOP for the issuance of CoAs quality management failed to detect these training deficiencies Zhejiang Jiuzhou Pharmaceutical Co., China During our October 21-24, 2013 inspection of your active pharmaceutical ingredient manufacturing facility, Zhejiang Jiuzhou Pharmaceutical Co., Ltd., and your import/export company Zhejiang Zonebanner Jiuzhou Imp. & Exp. Co., Ltd., both located at No. 99 Waisha Road, Taizhou, Zhejiang Province, China, an investigator from the U.S. Food and Drug Administration (FDA) identified deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs). These deviations cause your APIs to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 351(a)(2)(B), in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP. CGMP VIOLATIONS Zhejiang Zonebanner Jiuzhou Imp. & Exp. Co., Ltd. (FEI 3010365339) 1. Failure to implement an effective system of managing quality and failure to transfer all quality or regulatory information received from the API manufacturer to your customers.
  25. 25. PHARMA UPTODAY 25 • Your trading company, hereafter referred to as Zonebanner, purchased APIs from an outside supplier and relabeled them without the oversight of a quality unit • Zonebanner had no quality system in place for the relabeling operations. 2. Failure of the quality unit to review batch production records prior to distribution of an API batch • your firm shipped finished lots without reviewing the batch records • your internal review would be unable to detect every instance for which your firm shipped materials whose batch records had not yet been reviewed. 3. Failure to document manufacturing operations at the time they are performed. • the entries for use, cleaning, and maintenance logbook for the days immediately prior to the inspection, our investigator found missing entries. • The employee later admitted that he had falsified this CGMP record and stated that he in fact had not performed the review, despite having signed the batch record as the QA reviewer and having released the batch. 4. Failure to adequately maintain equipment in a state appropriate for its intended use in the manufacture of APIs. o investigator noted a leak in the purified water (PW) system o pieces of manufacturing equipment in need of repair. AUDIT FINDINGS - EMA Non Compliance Reports 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 explanation, the running of “trial testing” prior to performing 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 qualification 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.
  26. 26. PHARMA UPTODAY 26 SIMS Società Italiana Medicinali Scandicci srl, Italy 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, GMP-non compliant 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, GMP-non compliant 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) • 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) Update 09/07/2014: Further request, the Company provided the list of APIs stored and dispensed in the unauthorised and GMP non-compliant areas, with the specification of which ones out of them were dispensed in the rooms. An assessment of these batches has been made and a rapid alert has been issued (RA IT/II/10/01) which takes into consideration that the potential risk of cross-contamination is not related to high potency or sensitizing APIs such as for instance beta-lactams, cytostatics or hormones. SCM PHARMA LIMITED, UK 1. A critical deficiency was cited regarding potential product cross contamination, this deficiency was divided into two sections : A. Potential chemical contamination, it was found that the company were manufacturing a potent cytotoxic (Amsacrine) product in the non-potent suite. Processes intended to contain the product had failed and cleaning process and verification were weak with contamination of general manufacturing areas seen. B. Potential microbial contamination. There were contaminated process media simulations that were not adequately investigated and root cause explained and mitigated. VHP sanitisation of the filling isolator inadequately controlled and validated and weaknesses in the environmental monitoring program. 2. A major deficiency regarding the change control program (not all changes were controlled appropriately) and investigations, which were poor in quality with regards to root cause analysis and corrective and preventative actions and were not performed in a timely manner. 3. A second major deficiency regarding maintenance of equipment and facilities with poor controls witnessed
  27. 27. PHARMA UPTODAY 27 Regulations of the Month Subpart I--Laboratory Controls § 211.167 Special testing requirements. (a) For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall be appropriate laboratory testing to determine conformance to such requirements. The test procedures shall be in writing and shall be followed. (b) For each batch of ophthalmic ointment, there shall be appropriate testing to determine conformance to specifications regarding the presence of foreign particles and harsh or abrasive substances. The test procedures shall be in writing and shall be followed. (c) For each batch of controlled-release dosage form, there shall be appropriate laboratory testing to determine conformance to the specifications for the rate of release of each active ingredient. The test procedures shall be in writing and shall be followed. § 211.170 Reserve samples. (a) An appropriately identified reserve sample that is representative of each lot in each shipment of each active ingredient shall be retained. The reserve sample consists of at least twice the quantity necessary for all tests required to determine whether the active ingredient meets its established specifications, except for sterility and pyrogen testing. The retention time is as follows: (1) For an active ingredient in a drug product other than those described in paragraphs (a) (2) and (3) of this section, the reserve sample shall be retained for 1 year after the expiration date of the last lot of the drug product containing the active ingredient. (2) For an active ingredient in a radioactive drug product, except for nonradioactive reagent kits, the reserve sample shall be retained for: (i) Three months after the expiration date of the last lot of the drug product containing the active ingredient if the expiration dating period of the drug product is 30 days or less; or (ii) Six months after the expiration date of the last lot of the drug product containing the active ingredient if the expiration dating period of the drug product is more than 30 days. (3) For an active ingredient in an OTC drug product that is exempt from bearing an expiration date under 211.137, the reserve sample shall be retained for 3 years after distribution of the last lot of the drug product containing the active ingredient. (b) An appropriately identified reserve sample that is representative of each lot or batch of drug product shall be retained and stored under conditions consistent with product labeling. The reserve sample shall be stored in the same immediate container-closure system in which the drug product is marketed or in one that has essentially the same characteristics. The reserve sample consists of at least twice the quantity necessary to perform all the required tests, except those for sterility and pyrogens. Except for those for drug products described in paragraph (b)(2) of this section, reserve samples from representative sample lots or batches selected by acceptable statistical procedures shall be examined visually at least once a year for evidence of deterioration unless visual examination would affect the integrity of the reserve sample. Any evidence of reserve sample deterioration shall be investigated in accordance with 211.192. The results of the examination shall be recorded and maintained with other stability data on the drug product. Reserve samples of compressed medical gases need not be retained. The retention time is as follows: (1) For a drug product other than those described in paragraphs (b) (2) and (3) of this section, the reserve sample shall be retained for 1 year after the expiration date of the drug product.
  28. 28. PHARMA UPTODAY 28 (2) For a radioactive drug product, except for nonradioactive reagent kits, the reserve sample shall be retained for: (i) Three months after the expiration date of the drug product if the expiration dating period of the drug product is 30 days or less; or (ii) Six months after the expiration date of the drug product if the expiration dating period of the drug product is more than 30 days. (3) For an OTC drug product that is exempt for bearing an expiration date under 211.137, the reserve sample must be retained for 3 years after the lot or batch of drug product is distributed. § 211.176 Penicillin contamination. If a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin, the non-penicillin drug product shall be tested for the presence of penicillin. Such drug product shall not be marketed if detectable levels are found when tested according to procedures specified in `Procedures for Detecting and Measuring Penicillin Contamination in Drugs,' which is incorporated by reference. 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”.

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