To recap the previous month's pharma highlights to Pharma Uptoday members, Monthly magazine Volume 6 has been released with News Uptoday New Guidance New MAPP Release Audit Findings 483 Observations - 483 of Impax Laboratories - 483 of Ipca Labs - 483 of Bausch & Lomb Inc - 483 of Alexion Warning Letters - Marck Biosciences Ltd. - The Compounding Shop Inc. - Zions Rx Formulations Services LLC. EMA Non-Compliance Reports - Renown Pharmaceuticals Pvt. Ltd., India - VETPROM AD, Bulgaria - SCM PHARMA LIMITED, UK Guest of the Month Dr. M Damodharan - Vice President Global Quality & Regulatory Regulations of the Month § 211.180 Subpart J--Records and Reports - General Requirements § 211.182 Subpart J--Records and Reports - Equipment cleaning & use log

1. VOLUME: 6 - ISSUE: SEP 2014 |
PHARMA UPTODAY
For feedback, suggestions & queries write
to us on “pharmauptoday@gmail.com”
‘Cultural change in our
mindset & working is
sought to come out from
the current data integrity
issues …’
‘Document everything &
execute apt investigation’
says
VP – Global Quality & RA -
Dr. M. Damodharan.
For complete interview refer
“Guest of the Month” column.

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Inside this issue
3 News Uptoday
13 New Guidance
17 New MAPP Release
19 Audit Findings
483 Observations
- 483 of Impax Laboratories
- 483 of Ipca Labs
- 483 of Bausch & Lomb Inc
- 483 of Alexion
Warning Letters
- Marck Biosciences Ltd.
- The Compounding Shop Inc.
- Zions Rx Formulations Services LLC.
EMA Non-Compliance Reports
- Renown Pharmaceuticals Pvt. Ltd., India
- VETPROM AD, Bulgaria
- SCM PHARMA LIMITED, UK
25 Guest of the Month Dr. M Damodharan - Vice President Global Quality & Regulatory
29 Regulations of the Month § 211.180 Subpart J--Records and Reports - General Requirements § 211.182 Subpart J--Records and Reports - Equipment cleaning & use log

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News Uptoday European Medicines Agency invites comments on new overarching guidance for the development of influenza vaccines
The European Medicines Agency (EMA) has released the second module of a new overarching guideline on influenza vaccines for a six-month public consultation.
The guidance published today covers the non-clinical and clinical requirements for the development of new influenza vaccines and aims to facilitate the prompt assessment of new vaccines. It follows the publication in April of a module on the quality requirements. The new modular guideline is intended to cover and update in one single, consolidated document the existing guidance on regulatory, quality, non-clinical and clinical aspects of the development of all types of influenza vaccines, in all epidemiological situations, i.e. seasonal, pandemic and pre-pandemic. It has been developed based on the experience gained from many years of seasonal vaccination campaigns, the 2009/2010 influenza A(H1N1) pandemic, requests for scientific advice received from vaccine developers and applications formarketing authorisation. The guidance provided applies to vaccines for which ample regulatory experience has been gained, as well as to some novel types of vaccines based on established surface antigens. The most notable changes introduced by the non-clinical and clinical module of theguideline include:
o new terminology for pandemic vaccines to replace the term pandemic mock up vaccine with „pandemic preparedness vaccines‟ and the term pre-pandemic vaccines with „zoonotic influenza vaccines‟;
o revision of criteria for the assessment of immunogenicity in favour of a broader evaluation of immune responses rather than the use of seroprotection rate and haemagglutination inhibition as the main tests for evaluation;
o introduction of effectiveness studies for seasonal influenza vaccines as requirements in the post- authorisation phase.
The guidance on enhanced safety surveillance for seasonal influenza vaccines, which was adopted as a stand- alone document in April 2014, will be annexed to this module following its finalisation.
Comments on the draft non-clinical and clinical module of the influenza vaccinesguideline are invited until 31 January 2015 and should be sent tovwp@ema.europa.eu using the form provided.
Source: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/07/news_detail_002151.jsp&mid=WC0b01ac058004d5c1 European Medicines Agency publishes first public summaries ofPaediatric Committee evaluations of paediatric investigation plans
Initiative increases transparency and public access to relevant information on medicines

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The European Medicines Agency (EMA) has published the first summaries for the public of the Paediatric Committee's (PDCO) evaluations of paediatric investigation plan (PIP) and waiver applications. The summaries published today relate to PIPs for a cell-based therapy for the treatment of non-traumatic osteonecrosis, a new medicine for the treatment of atopic dermatitis and a waiver for a medicine for eye diseases. From now on, the Agency will publish such summaries for each PDCO evaluation of an application for a PIP or a full waiver. The summaries describe the proposal from the applicant for the development of their medicine in children, the PDCO's conclusion on the potential use of the medicine in the paediatric population, the plan agreed between the committee and the applicant at the completion of the procedure (including any partial waivers or deferrals) and the next steps.
This new type of document increases the amount of public-friendly information published by the EMA on its assessments of medicines that are still under development, before they are authorised for use in the European Union. These summaries complement the public-friendly information already made available by the Agency, including public summaries of European public assessment reports, risk management plans and opinions on orphan designation.
Since the Paediatric Regulation came into force in the EU in 2007, pharmaceutical companies have had a legal obligation to develop all new medicines for children as well as for adults in line with an agreed PIP, unless they obtain an exemption (waiver). The PDCO reviews all applications for PIPs and waivers and issues an opinion on the clinical studies, pharmaceutical forms and tests that must be performed in children. These studies may be deferred, for example if the PDCO considers that experience in adults is needed before paediatric clinical trials are conducted. Additionally, the PDCO may grant a full or partial waiver from the obligation to develop a medicine in paediatric populations when the condition concerned does not exist in children, when the medicine is not likely to offer any benefit for children, or when it is unsafe to use it in children. This helps to avoid unnecessary paediatric studies.
Source: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/07/news_detail_002150.jsp&mid=WC0b01ac058004d5c1 Fresenius: US supply from troubled Indian plant to restart in Q3 Fresenius Kabi has recommenced production at a troubled Indian facility and expects to start shipping APIs to the US in the next few weeks. The US Food and Drug Administration (FDA) observed management and staff manipulating quality control data at Fresenius Kabi‟s Kalyani, India active pharmaceutical ingredient (API) plant, amongst a number of GMP violations cited in a July 2013 warning letter . At the time, the firm responded by sacking QC personnel involved with the cover up and halted production at the plant - which makes some ingredients used in the firm's cancer drugs – but during a conference call Sunday to discuss Q2 2014 results, Fresenius Chairman Mark Schneider said manufacture had recommenced. “Shipments to destinations outside of the US have commenced in Q2,”he said. “We expect shipments to the US later this quarter.”

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He continued to tell investors the FDA is yet to have reinspected the site. However, “based on past inspection intervals we expected an FDA audit at the site at any time. Earlier this year the UK’s MHRA inspected the site successfully and confirmed GMP compliance.” Europe to boost cooperation with international partners on generics
European system to be used as model to facilitate assessment of medicines The European Union‟s decentralised procedure is being used as a model to accelerate the assessment of applications for generic medicines as part of the International Generic Drug Regulators Pilot (IGDRP). The European Union (EU) is leading an international pilot project through which, upon request from a generic pharmaceutical company, it will share the assessment reports generated as part of the decentralised procedure in real time with collaborating regulatory agencies outside the EU. By offering to share its assessment reports, the EU aims to reinforce collaboration and information-sharing between regulatory authorities across the world, contributing to facilitating and strengthening the scientific assessment process for medicines. This should enable medicines to be authorised in different territories in a coordinated way at approximately the same time. The first phase of the pilot project will involve the EU, Australia, Canada, Chinese Taipei and Switzerland.
Other members of the IGDRP may decide to take part in the pilot programme at a later stage. These include Brazil, China, Japan, Korea, Mexico, New Zealand, Russia, Singapore and South Africa. The European Directorate for the Quality of Medicines & Healthcare (EDQM) and the World Health Organization (WHO) participate as observers.
Further information about how to participate in the pilot programme can be found on the website of the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh). This initiative is one of the work packages of the IGDRP. Other areas of cooperation in which the EU is involved include work sharing possibilities in the area of active substance master file, inspection of sites conducting bioequivalence and bio-analytical studies and information sharing on pharmaceutical quality issues. The IGDRP was launched in April 2012 to promote collaboration and convergence in generic medicines regulatory programmes in order to address the challenges posed by increasing workloads, globalisation and complexity of scientific issues. President’s Emergency Plan for AIDS Relief (PEPFAR) In 2003, Congress passed the President‟s Emergency Plan for AIDS Relief (PEPFAR), which targeted the prevention, treatment, and care of people living with HIV/AIDS in Africa, Asia, and the Caribbean. PEPFAR is now the single greatest supporter of treatment for AIDS in the developing world. PEPFAR policy dictated that it could only purchase prescription drugs approved by a stringent regulatory authority, such as the U.S. Food and Drug Administration. However, the most commonly used drugs in the AIDS-affected regions before PEPFAR were generics not approved or available in the United States. Showing flexibility rare for a regulatory agency, FDA created an innovative approach that was considered by many to be a game changer: tentative approval. The game-changer: Tentative approval A drug application with tentative approval must show that the product meets the same standards as drugs approved for the U.S. population. As a result, existing products that meet all FDA quality, safety and scientific standards are approved as generic drugs and are eligible for purchase with PEPFAR funds. Tentative approval has lead to more than 150 antiretroviral drugs being integrated into many PEPFAR treatment programs. Through the efforts of FDA and its world-wide partners, the United States directly supports life-saving antiretroviral treatment for more than 3.9 million men, women and children worldwide.

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Not the only breakthrough To streamline production, FDA pulled together manufacturers interested in producing the needed products and explained, step-by-step, how to submit applications and set up manufacturing processes to be successful. The agency expedited these applications, travelled around the world to inspect facilities and made sure there were systems in place to produce quality HIV drugs. FDA initiatives also helped to revolutionize treatment for resource-poor settings by simplifying HIV/AIDS treatment. The agency approved applications for fixed-dose combinations and co-packaged products. Both were significant innovations because they reduce the number of pills taken each day. Some can even be dispersed in water for children who are not able to swallow tablets. Because these drug products are easier to manage – for both patients and health workers – patients are more likely to take their medicines properly, at the right dose and for the scheduled length of time. Before the passage of PEPFAR, only 50,000 people in Sub-Saharan Africa were receiving treatment for HIV/AIDS. And the typical cost of antiviral treatment for one person was $10,000 per year; now the cost has come down to under $200 per person, enabling over 200,000 more people to receive treatment under the PEPFAR program. Source: http://www.fda.gov/Drugs/ResourcesForYou/SpecialFeatures/ucm312754.htm Concept paper on transferring quality control methods validated in collaborative trials to a product / laboratory specific context This concept paper proposes the development of guidance on how data can be used to support laboratory- and product-specific validation of 3Rs (reduction, replacement and refinement) methods in order to facilitate implementation of methods for product-specific testing. The paper would also provide guidance on how published data from collaborative studies can be used to support in-house validation for other laboratories not involved in the collaborative work. For more details browse: http://www.ema.europa.eu/ema/doc_index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500169977&murl=menus/document_library/document_library.jsp&mid=0b01ac058009a3dc June ANDA Submissions Ran Industry Dry for July! With what seemed like the entire industry trying to beat the June 20, 2014 submission deadline ahead of the ANDA new stability requirements set to take effect that day, a record of 635 ANDAs were submitted in June. Now it looks like there will be some reload time before OGD sees the normal flow of ANDAs coming in. Just like the drought in Southern California, the July 2014 submission figures looked like the 5 minute rain shower we had last week that produced no measureable rainfall and produced a meager 4 ANDA submissions – almost no measureable ANDAs compared to previous months this Fiscal Year. This will give OGD some room to maneuver around the large number of submissions that have flooded OGD in the previous months. The next big submission month is likely going to be October 2014, the beginning of FY 2015 and the month the GDUFA metrics take effect for the cohort year 3 submissions. Another reason we may expect more ANDAs beginning that month is that the GDUFA fees for ANDA submissions dropped a bit due to the high submission rate over FY years 2011, 2012, and 2013. I don‟t think that the almost 1500 ANDAs submitted thus far in FY 2014 really played into the calculation of the 2015 ANDA GDUFA fee figure. It will be interesting to see how the submission numbers trend after October 31.

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Also, on the positive side, OGD received 134 amendments to original ANDAs, which is slightly below this fiscal year‟s average of 146, although OGD only approved 18 ANDAs in July and issued 87 complete response letters, which is a bit below their FY 2014 monthly average of 109. We are all sure that OGD anticipates that the approval numbers and (Complete Response Letters) CRLs will increase steadily as OGD and OPQ staff become fully trained and as the October 1, 2014 start of cohort year metrics begins. Source: http://www.lachmanconsultants.com/june-anda-submissions-ran-industry-dry-for-july.asp MHRA GMP Update: Short-term storage of ambient and refrigerated medicinal products and the requirement for a wholesale dealers authorisation (WDA) The EU GDP Guidelines define wholesale distribution as; “…all activities consisting of procuring, holding, supplying or exporting medicinal products…” The annexed Glossary of Terms defines holding as “storing medicinal products”. Medicinal products should therefore only be stored on premises that are covered by a Wholesale Distribution Authorisation. However, there are certain cases where medicinal products are held for short periods of time during transportation and prior to onward shipment e.g. in the transportation vehicle at motorway service stations or in overnight freight depots. In such instances it has been determined that, as a matter of policy, a site does not have to be named on a licence where ambient products are stored for less than 36 hours. Sites holding ambient products in excess of 36 hours must be licensed. This policy applies only where ownership of the products has not been transferred to the person carrying out the storage activities. Where ownership has been transferred, this is supply and as such the receiving site must be licensed. It is also important to note that, where wholesaling activities other than storage are being carried out, the site should be named on the relevant licence. This includes the handling of returned goods and where decisions are made regarding suitability for resale, as well as the usual activities of picking against orders. Sites where refrigerated products are held, even when this is for less than 36 hours, must be licensed. The exception will be where these products are transported and stored overnight in continuously refrigerated vehicles. The provisions of Chapter 9.2 of the EU GDP Guidelines must also be observed. MHRA position on freight consolidation depots (freight forwarders) Since the application of the Falsified Medicines Directive 2011/62/EU in January 2013 (transposed into UK law through The Human Medicines (Amendment) Regulations 2013 [SI 2013/1855] which came into force on 20 August 2013), both the act of export of a human medicine and the holding of a human medicine intended for export, by way of wholesale distribution, now requires authorisation. The result of the change in European Legislation means that a number of companies and their sites that were not previously regulated now require a wholesale distribution authorisation (WDA(H)).

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The GDP Inspectorate is raising awareness of the impact of the new regulations to those parties that are either directly or indirectly affected and any freight consolidator or freight forwarder either in the air, sea or road transport sector that is either holding ambient medicinal products on site for more than 36 hours or has cold room facilities will require a Wholesale Distribution Authorisation WDA(H) in order to comply with the Human Medicines Regulations 2012 [SI 2012/1916] (as amended) and with the Falsified Medicines Directive 2011/62/EU. Dr. Reddy's Files First Patent Challege Against Teva's Copaxone 40mg Indian generics firm Dr. Reddy‟s has filed the first patent challenge against Teva‟s blockbuster multiple sclerosis drug Copaxone‟s 40 mg, introducing a new chapter into the Israeli drugmaker‟s efforts to protect its multibillion dollar product. Teva confirmed receipt of a Dr. Reddy‟s Paragraph IV ANDA Aug. 7, and said it would file a patent infringement lawsuit triggering a 30-month stay of approval under Hatch-Waxman. Two of the Copaxone (glatiramer acetate) patents run until 2030, Teva said. However, those aren‟t the patents the drugmaker is likely worried about. The rest of the drug‟s patents expired in May, including all of the ones protecting its 20 mg version. Teva has spent years fighting to protect Copaxone, which generated $4.3 billion last year. Those efforts have included a patent infringement lawsuit against a proposed generic of the Copaxone 20 mg version that is bound for the U.S. Supreme Court this fall. In addition, Teva has filed seven different citizen petitions and even a lawsuit against the FDA seeking more stringent testing of would-be Copaxone copies, as well as efforts to shift patients from the 20 mg version to the 40 mg one. The lawsuit against the FDA was tossed last month. Roxane Unable to Block Hetero's Generic PhosLo Subsidiaries of generics maker Hetero Drugs can move forward with generic versions of kidney drug PhosLo despite an ongoing lawsuit brought by patent owner Roxane Laboratories. A U.S. District Court in New Jersey denied a motion Aug. 6 from Roxane to block the generics as the case continues, finding that the patent infringement lawsuit has little chance of success. Nor would market entry by Hetero subsidiary Camber Pharmaceuticals disrupt a status quo, which already has several generic versions of PhosLo (calcium acetate) on the market, the judge ruled. Fellow litigant and Hetero subsidiary InvaGen Pharmaceuticals‟ generic version is one of them. Roxane, itself a generics maker, holds the patent rights on PhosLo‟ active ingredient and markets its own generic version. Several other companies also market generic versions, the judge noted, meaning that Roxane‟s claims of price erosion from further generic entry are unlikely. The ruling also dealt the lawsuit‟s future prospects a severe blow by finding many of Roxane‟s infringement claims lacking, especially in noting that the PhosLo patent apparently covers a slightly different capsule size than the versions employed in Camber and InvaGen‟s ANDAs. API sales down 81% as Ranbaxy feels fallout from US import alerts Ranbaxy has reported a 14% drop year-on-year of overseas revenues attributed in part to the voluntary suspension of shipments from its Toansa and Dewas facilities API facilities. For the first quarter of fiscal year 2014-5, Ranbaxy announced consolidated sales of INR 23.7bn ($390m), comprising of INR 6.2bn worth of sales in India (up 12% year-on-year) and INR 17.5bn from overseas (down 14%).

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The fall in overseas revenues was attributed to an 81% drop in sales of active pharmaceutical ingredients (APIs), mostly from the firm‟s plants in Toansa and Dewas – both India – following regulatory clampdowns and a voluntary suspension of shipments still ongoing. The Dewas plant was one of three hit with a US Food and Drug Administration (FDA) consent decree in 2012 , whilst Toansa received animport ban in January . Whilst Toansa had its GMP certificate reinstated by the EMA in June , the firm is still feeling the impact from the voluntary halt in production. “I think over the period of next couple of quarters, we should see absolute normalization of these operations for our API business,” CEO Arun Sawhney said when asked in a conference call about possible timelines for the return of full production and shipping. He continued, telling investors the firm was currently supplying to several markets around the world, both regulated and otherwise. For the quarter, API sales stood at INR 466m compared to INR 2.3bn in the same quarter last year. Sawhney also spoke of the administrative subpoena issued by the US Department of Justice (DOJ) in March this year, seeking further information as to operations at the Toansa plant. “It is directed towards getting some documents and questions and some information relating to the Toansa import alert related matters,” he said. “It is not nothing more than that as far as our knowledge goes at this stage… whether it will develop further etc., we do not know [until] after we had provided the information to DOJ.” Drugmaker Dr Reddy's under scanner for packaging violations Drugmaker Dr Reddy's Laboratories has come under the scanner of Department of Justice of USA for alleged violations of some provisions of Consumer Product Safety Act involving child resistant packaging regulations. The company has denied the Consumer Product Safety Commission's (CPSC) allegations in the matter. The Indian drug major said in a filing with US Securities and Exchange Commission (SEC) that the issue is related to compliance with requirements of special packaging for child resistant blister packs for six products sold by the company in the United States from 2002 through 2011. The filing said: "The company disagrees with the CPSC's allegations and is engaged in discussions with the CPSC regarding its compliance with the regulations. Simultaneously, the Department of Justice (the DOJ) is also currently investigating a complaint related to these issues under the Federal False Claims Act. "At this stage of the proceedings, the Company cannot conclude that the likelihood of an unfavourable outcome is either probable or remote." In May 2012, CPSC had requested Dr Reddy's Laboratories Inc, a wholly owned subsidiary of the Company in the US, to provide certain information with respect to compliance with requirements of special packaging for child resistant blister packs for six products sold by the company in the US during the period commencing in 2002 through 2011. The company provided the requisite information. The CPSC subsequently alleged in a letter dated April 30, 2014 that the company violated the Consumer Product Safety Act (CPSA) and the Poison Prevention Packaging Act (PPPA) and intends to seek civil penalties. Specifically, the CPSC asserted, among other things, that from or about August 14, 2008 through June 1, 2012, the company sold prescription drugs having unit dose packaging that 'failed to comply' with the CPSC's special child resistant packaging regulations under the PPPA and failed to issue general certificates of conformance. In addition, the CPSC asserted that the company violated the CPSA by failing to immediately advise the CPSC of the alleged violations.

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Dr Reddy's however said that no provision is made in the company's unaudited condensed consolidated interim financial statements as of June 30, 2014. An unfavourable outcome in these matters could result in significant liabilities, which could have a material adverse effect on the company, it further said. Change in mindset key to thwart recurring integrity issues for Indian pharma during global audits: SM Mudda
Indian pharma industry is currently facing the challenge of dealing with data integrity issues during the international regulatory inspections despite the remarkable progress of the sector in the global arena as a leading manufacturer of active pharmaceutical ingredients (APIs) and formulations. The need of the hour is to move away from the traditional approach of product quality and good manufacturing practices (GMP) compliance which does not seem to encourage adoption of modern system-based approach and focus on behavioural aspects rather than technical issues, said SM Mudda, executive director – technical & operations Micro Labs Limited. It is time that the Indian pharma counsel its personnel. It should not restrict its focus only on need–based, risk averse and inspection-oriented compliance. Instead, the industry would need to embark on an employee engagement exercise and take immediate steps to create a quality mindset right from the management to shop floor, he added. “In terms of Maslow's theory of motivation, the motivating factors in key professionals, despite demonstrating their ability to manufacture best-quality products, unfortunately appears to have come down to the level of merely fulfilling basic needs. It involves need for protection rather than growth needs, where each individual is self- motivated to achieve personal excellence. The fear of failure appears to be one of the contributing factors for professionals in view of the overall criticism of the practices followed, said Mudda in his presentation on „ Motivating quality and operation teams to quality systems compliance‟ at the Indian Pharmaceutical Association Platinum jubilee event recently. While steps are initiated in creating a culture of quality and compliance in the industry, the immediate concern seems to be to create a hygienic environment where every individual is encouraged to comply with the regulatory requirements keeping patient safety in mind. Quoting Deming's 94/6 Rule, he said that 94 per cent problems are caused by the system and 6 per cent by the individual. At least 85 per cent efficiency of the operating staff comes from the work environment and balance from his skills, said Mudda adding that adoption of Pharmaceutical Quality System or ICH Q 10 is the way forward to create a conducive environment which encourages quality culture across the organisation. Therefore, developing second level leadership which is motivated to implement the top management commitment to quality, in letter and spirit, is necessary, he noted. In order to bring back the reputation of high quality standards, Indian pharma industry needs to ensure reducing the fear of errors. The industry will need to foster a culture of error management. This would help in fearless and transparent communication of errors where mistakes are analysed and lessons are learnt from the slip-ups. There is need to help the workforce to do a better job, break down barriers between departments, eliminate management by objectives and substitute it with leadership, said Mudda.

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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.

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News
Articles
Warning letters
483's
GMP
Presentations
Guideline
Regulations
Drug category
Non Compliance Reports
Basics
Quality tools
Webinars
VIdeos

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New Guidance Revision of EDQM “Guideline on requirements for revision/renewal of certificates of suitability to the European Pharmacopoeia monographs” The EDQM has revised the “Guideline on requirements for revision/renewal of certificates of suitability to the European Pharmacopoeia monographs”: - to include the requirements of the revised EU guideline on “Stability testing for applications for variations to a marketing authorisation” (EMA/CHMP/CVMP/QWP/441071/2011 Rev 2). - to describe the types of revision to be submitted when a CEP for a starting material is used in an application for another CEP(cf.PA/PH/CEP (14) 06). The revised document has an implementation date of 1st October 2014. Source: http://www.edqm.eu/en/Revision-of-EDQM-%E2%80%9CGuideline-on-requirements-for-revisionrenewal- of-certificates-of-suitability-to-the-European-Pharmacopoeia-monographs%E2%80%9D-1587.html?mbID=219 Questions and answers on wheat starch containing gluten in the context of the revision of the guideline on excipients in the label and package leaflet of medicinal products for human use Wheat starch is produced from wheat flour by removing proteins including gluten, meaning that wheat starch only contains trace amounts of gluten and other proteins. These questions and answers include proposals for new or updated information for the labelling and package leaflet regarding gluten as an excipient in human medicines.
Source: http://www.ema.europa.eu/ema/doc_index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500170476&murl=menus/document_library/document_library.jsp&mid=0b01ac058009a3dc Guidance for Industry: Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act This guidance is intended to assist sponsors who are developing biological products, sponsors of biologics license applications (BLAs), and other interested parties in providing information that will help the Agency determine the date of first licensure for a reference product under 351(k)(7)(C) of the Public Health Service Act (PHS Act), as added by the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). Under 351(k)(7), licensure of an application for a biosimilar or interchangeable product under 351(k) of the PHS Act (also known as a 351(k) application) may not be made effective by FDA until the date that is 12 years after the date on which the reference product referred to in the 351(k) application was first licensed under section 351(a) of the PHS Act. In addition, a 351(k) application may not be submitted to FDA for review until 4 years after the date of first licensure of the reference product. This period of time in which a 351(k) application may not be licensed (or submitted for review) is known as the reference product exclusivity period. Thus, a decision under 351(k)(7)(C) regarding the date of first licensure of a reference product submitted under 351(a) is, in effect, a decision on eligibility for reference product exclusivity and on the date on which such exclusivity begins to run. Source : http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM407844.pdf

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PIC/S adopts EU GDP Guidelines The Pharmaceutical Inspection Co-operation Scheme PIC/S has published a PIC/S Guide to Good Distribution Practice for Medicinal Products (PE 011-1). This Guide is based on the EU GDP-Guidelines (2013/C 343/01) and quotes the EU Guide almost completely. However, EU specific references have been deleted and the term "must" is often replaced by the term "should". A dedicated Responsible Person is not introduced by the PIC/S document. It talks about "designated responsible person(s)" or "designated person(s)". Chapter 2.2 "Responsible person" of the EU GDP Guide is not quoted in the PIC/S document. Also import activities are covered by the PIC/S Guide. EU GDP Chapter 5.9 "Export to third countries" has been amended and also covers import activities. Chapter 10 "Specific provisions for brokers" has been deleted completely. The structure of the PIC/S document has been aligned with the structure of the EU GMP Guidelines, including 9 chapters:  Chapter 1 Quality Management  Chapter 2 Personnel  Chapter 3 Premises and Equipment  Chapter 4 Documentation  Chapter 5 Operations  Chapter 6 Complaints, Returns, Suspected Falsified Medicinal Products and Medicinal Product Recalls  Chapter 7 Outsourced Activities  Chapter 8 Self-Inspections  Chapter 9 Transportation As with the EU Guidelines, Risk Assessments will become a key tool for implementation of the new requirements. PE 011-1 is now an official PIC/S guidance document. This does not mean that it is automatically in force in all PIC/S member states. It is a non-binding guidance and PIC/S Participating Authorities need to decide whether it should become a legally-binding standard and then implement it accordingly. Implementation should take into consideration national legislation. In some PIC/S countries for example, importation may fall under GMP and a manufacturer's license may be required. Currently, PIC/S has 46 Participating Authorities, including most EU Member States, Switzerland, Japan and the USA. Guidance for Industry: Upper Facial Lines: Developing Botulinum Toxin Drug Products The purpose of this guidance is to assist sponsors in the clinical development of therapeutic biological products, specifically botulinum toxins, for the temporary improvement in the appearance of upper facial lines, such as glabellar lines or lateral canthal lines (LCLs). This guidance addresses the FDA‟s current thinking regarding the overall development program and clinical trial designs of botulinum toxin drug products to support approval for an upper facial lines indication. The information presented is intended to help sponsors plan clinical trials, design clinical protocols, and implement and appropriately monitor the conduct of clinical trials. This draft guidance is intended to serve as a focus for continued discussions among the Division of Dermatology and Dental Products, pharmaceutical sponsors, the academic community, and the public. Development plans should be discussed with the review division before embarking on trials to ensure that the clinical trial design meets defined objectives. Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM407983.pdf

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EMA NIR Guideline finalized Near Infrared Spectroscopy (NIRS) is one of the key technologies applied in PAT (Process Analytical Technology) processes. NIRS can also be part of "Real Time Release Testing (RTRT)" strategies. Since the application of NIRS requires an understanding of the products and processes, it is widely used in Quality by Design (QbD) approaches. In January 2014 the EMA now published the final "Guideline on the use of Near Infrared Spectroscopy (NIRS) by the pharmaceutical industry and the data requirements for new submissions and variations". This document contains requirements for the development, calibration, and validation of NIRS methods, both for qualitative and quantitative analyses. And it also applies to PAT applications. The guideline specifically also refers to the submission of NIRS methods or to variations to approved methods. In addition, the EMA has published an addendum to this guideline on 5 June 2014 to clarify the scope of application of the guideline. In this addendum it is stated: Changes within the approved scope of the NIRS method are only subject to GMP. Changes outside of the approved scope of the NIRS method are subject to the rules of variation. The addendum was intentionally created in addition to introduce a fictitious example to show how changes are supposed to be handled in accordance with this guideline. A NIRS method for the release testing of an active substance in a finished product (assay and content uniformity in a tablet) is used as an example. For this example, table 2 lists the changes within the scope of approved NIRS methods. Table 3 shows changes that are outside the approved scope. Source: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/06/WC500167967.pdf Guidance for Industry: Clinical Pharmacology Labeling for Human Prescription Drug and Biological Products — Considerations, Content, and Format This guidance is intended to assist applicants in preparing the CLINICAL PHARMACOLOGY section of product labeling to meet regulatory requirements (21 CFR 201.57(c)(13)) and ensure appropriate consistency in the format and content of this section for all prescription drug products approved by FDA.The guidance provides recommendations to applicants submitting new drug applications (NDAs) (including applications submitted under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(b)(2)), abbreviated new drug applications (ANDAs), supplements to approved NDAs, biologics license applications (BLAs), and supplements to BLAs, who intend to prepare or amend the clinical pharmacology information in the labeling for human prescription drug or biological products. Not all of the information identified in this guidance for inclusion in the CLINICAL PHARMACOLOGY section of product labeling will be applicable for every drug; rather, the guidance provides a general framework and set of recommendations that should be adapted to specific drugs and their conditions of use. For clinical pharmacology information presented in other parts of labeling (see section III.B of this guidance), applicants should consult other relevant guidances for current perspectives on best labeling practices. Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM109739.pdf Guidance for Industry: Immunogenicity Assessment for Therapeutic Protein Products This guidance is intended to assist manufacturers and clinical investigators involved in the development of therapeutic protein products for human use. In this document, FDA outlines and recommends adoption of a risk- based approach to evaluating and mitigating immune responses to or adverse immunologically related responses associated with therapeutic protein products that affect their safety and efficacy. Any given approach to assessing

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and mitigating immunogenicity is determined on a case-by-case basis and should take into consideration the risk assessment we describe. For the purposes of this guidance, immunogenicity is defined as the propensity of the therapeutic protein product to generate immune responses to itself and to related proteins or to induce immunologically related adverse clinical events. Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM338856.pdf FDA posts Draft Guidance for Industry: Controlled Correspondence Related to Generic Drug Development FDA displayed a notice in the Federal Register announcing the availability of a new draft guidance for industry:  Controlled Correspondence Related to Generic Drug Development This guidance provides information regarding the process by which generic drug manufacturers and related industry can submit correspondence to FDA requesting information related to generic drug development. This guidance also describes FDA‟s process for providing communications related to such correspondence. FDA is issuing this draft guidance as part of the Agency‟s implementation of the Generic Drug User Fee Amendments of 2012. A pre-recorded webinar explaining this draft guidance is available at :  CDER Small Business and Industry Assistance (CDER SBIA) Webinar “Draft Guidance for Industry on Controlled Correspondence Related to Generic Drug Development” – August 26, 2014 Submit electronic comments on the draft guidances to the Federal Register docket. On July 9, 2012, the Generic Drug User Fee Amendments of 2012 (GDUFA) was signed into law by the President of the United States of America. GDUFA was designed to speed the delivery of safe, effective, and high-quality generic drugs to the public. This program will bring greater predictability and timeliness to the review of generic drug applications. GDUFA is based on an agreement negotiated by FDA and representatives of the generic drug industry. New MAPP Release MAPP on NDAs and BLAs: Communication to Applicants of Planned Review Timelines This MAPP establishes procedures for informing applicants of the planned review timeline, including the goal dates for discussion of labeling and postmarketing requirements (PMRs) and commitments (PMCs), for original new drug applications (NDAs), biologics license applications (BLAs), and efficacy supplements submitted to the Center for Drug Evaluation and Research (CDER). Source: http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/StaffPoliciesandProcedures/ucm081995.pdf

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Manual of Policies and Procedures (MAPP) on Criteria and Procedures for Managing the Review of Original ANDAs, Amendments and Supplements This MAPP describes the criteria and procedures by which the Office of Generic Drugs (OGD), Division of Project Management leadership will manage the review of generic drug submissions. Source: http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProcedures/UCM407848.pdf Manual of Policies and Procedures (MAPP) on Prioritization of the Review of Original ANDAs, Amendments, and Supplements This MAPP describes how the review of abbreviated new drug applications (ANDAs), ANDA amendments, and ANDA supplements will be prioritized for review within the Office of Generic Drugs (OGD) and the Office of Pharmaceutical Science (OPS)/Office of Pharmaceutical Quality (OPQ). This MAPP is a revision of MAPP 5240.3, Review Order of Original ANDAs, Amendments, and Supplements (October 18, 2006). This MAPP also supersedes MAPP 5240.1, Requests for Expedited Review of Supplements to Approved ANDAs (November 1, 1995). Information relevant to this MAPP is contained in the Draft Guidance for Industry, ANDA Submissions: Amendments and Easily Correctable Deficiencies Pursuant to GDUFA (July 11, 2014) and the Draft Guidance for Industry, Prior Approval Supplements Pursuant to GDUFA (July 11, 2014). Source: http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProcedures/UCM407849.pdf Manual of Policies and Procedures (MAPP) on Clarification Teleconferences Between Sponsors, Applicants, or Master File Holders And the ONDQA Review Team This MAPP establishes policies and procedures for the Office of New Drug Quality Assessment (ONDQA) within the Office of Pharmaceutical Science (OPS) to schedule, hold, and document clarification teleconferences between sponsors, applicants, or master file holders, and the ONDQA review team. This MAPP also provides a description of such teleconferences, as well as the circumstances where they can be appropriate and beneficial to the review process. The policies and procedures described in this MAPP are intended to facilitate timely and effective verbal communication between sponsors, applicants, and master file holders, and the ONDQA review team, and to increase the overall efficiency of the chemistry, manufacturing, and controls (CMC) and/or biopharmaceutics review process. These policies and procedures are also intended to provide a balance between ONDQA‟s resources, review workload and timelines, and the need for and benefit of such teleconferences. Source: http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProcedures/UCM407749.pdf

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AUDIT FINDINGS - 483 Observations Firm Name 483 Observation Scientific Botanicals Company, Inc. You did not implement a system of production and process controls that covers all stages of manufacturing, packaging, labeling and holding of dietary supplements to ensure the quality of the dietary supplement. Fontarome Chemical, Inc. Written records of investigations into unexplained discrepancies do not always include adequate conclusions and follow-up. Pharmaceutical Innovations, Inc. A process whose results cannot be fully verified by subsequent inspection and test has not been adequately validated according to established procedures. Hospira, Inc. Control procedures are not established which validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Zoetis P&U, LLC Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written and followed. Fermion Oy Laboratory documents were not reviewed by a quality control manager per your SOP. Fragrance Manufacturing, Inc., dba FMI You did not provide adequate documentation of your basis for determining that compliance with the specification you selected for the limits on contamination that may adulterate or that may lead to adulteration of the dietary supplement will ensure that the finished batch of dietary supplement will not be adulterated as a result of such contamination. Shionogi & Co., Ltd. Validation of the aseptic processing design and construction is not complete. Pure Source, Inc. Control procedures are not established which validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.
Impax Laboratories Inc – 483
1. There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed.
2. The accuracy, sensitivity, specificity and reproducibility of test methods have been established and documented.
3. Written procedures for cleaning and maintenance fail to include description in sufficient detail of methods, equipment and materials used and instructions for protection of clean equipment from contamination prior to use.
4. Appropriate controls are not exercised over computers or related systems to assure that changes in master production and control records are instituted only by authorized personnel.
5. The responsibilities and procedures applicable to the quality control unit are not fully followed.
6. Buildings used in the manufacturing and holding of a drug product are not maintained in a good state of repair.
7. Changes to written procedures are not drafted, reviewed and approved by the appropriate organizational unit.

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USFDA lists 6 deviations on Ipca Labs' Ratlam API unit  Two of the observations detailed severe data integrity issues in the plant. Moreover, there are observations indicating senior staff involvement in data falsification.  Quality system issues also date back to 2011 inspection that cited similar issues.  There are issues overwriting previous raw data and falsifying batches being placed along with instances of manipulating integration parameters so as to achieve desirable results.  Another instance posing serious threat was noted in the form 483 where USFDA states that they found analysts who were backdating or falsifying temperature records and when there were questioned on why they were doing it, they said, they were forced to falsify these records by the direct supervisor.  In addition, an event of power supply disconnect for four hours took place wherein the quality assurance assessment determined an out of trend for unknown impurity.  Serious threats can be raised for Ipca Labs if these issues are not resolved satisfactorily as FDA has shown zero tolerance in the past for data integrity lapses. Bausch & Lomb Inc, 483 FINISHED PHARMACEUTICALS 1. Specifically, integrity testing of the vent filters on the [REDACTION] Hot Purified Water (HPW) tanks was not conducted during the [REDACTION] month interval between June 2005 and March 2006 per SOP # 50-095-08. 2. Written procedures are not followed for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product. 3. The written stability program for drug products does not include meaningful and specific test methods. 4. Employees are not given training in the particular operations they perform as part of their function. 5. 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. 6. Procedures for controlling the storage of product in storage areas and stock rooms were not established to prevent mix-ups, damage, other adverse effects. 7. Procedures have not been documented to prevent contamination of equipment or product by certain substances. Reinspection lands Alexion with 483 for Soliris plant A US FDA reinspection of Alexion’s Rhode Island facility hit with a warning letter last year has resulted in a Form 483 with three observations. The Smithfield, Rhode Island facility is owned and operated by Alexion as one of three plants that manufacture the human monoclonal antibody drug Soliris (eculizumab) for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). In March 2013, the facility was hit by a US Food and Drug Administration (FDA) warning letter after six lots of the API for the drug were found to be contaminated with the bacteria Bacillus thuringiensis and the microorganism Acinetobacter radioresistens. Since then the firm has issued several recalls of what - at approximately $600,000 per patient per year - is the world‟s most expensive drug, but last month CEO Leonard Bell told investors during Alexion‟s second quarter results the firm was awaiting a reinspection following “continued improvements” at the site. However, according to a statement sent to Biopharma-Reporter.com by spokesman Irving Adler, the facility was reinspected by the FDA during the week of August 18, which issued a Form 483 with three inspectional observations, none of which were repeat observations from the original warning letter.

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“The three observations include a need for enhanced training around gowning procedures, more frequent environmental monitoring, and processes related to identification of the definitive root cause of a prior bioburden excursion,”. “We continue to manufacture products, including Soliris, in Smithfield and other facilities,” he continued, “and we believe that the supply of Soliris to patients will not be interrupted.” The two other facilities making Soliris are operated by Lonza in agreements that stretch until 2019. We contacted the Switzerland-based contract manufacturing organisation (CMO) to ask if Soliris capacity has been increased on the back of Alexion‟s manufacturing problems, but a spokesman told us the firm was “not in a position to comment,” on this or the process involved in making the MAb. However, according to Alexion‟s 2013 annual report , the “manufacture of Soliris is difficult” as it“requires a multi- step controlled process and even minor problems or deviations could result in defects or failures.” FDA Warning letters Warning letter : Marck Biosciences Ltd. 1. Your firm failed to prepare batch production and control records for each batch of drug product that include documentation of each significant step in the manufacture, processing, packaging, or holding of the batch (21 CFR 211.188(b)).  “unofficial” visual inspection records, signed by production personnel, with data that is different from the official batch records reviewed by your firm‟s quality unit  unofficial record completed by production personnel showed 200 units failing to meet specifications.  unable to demonstrate that all units with quality defects were in fact rejected  production personnel add extra units into the (b)(4) unit and lower the number of rejected units on the official paperwork to account for these extra units  The inspection revealed your firm‟s use of scratch paper containing critical manufacturing data. The data on these scratch paper records did not always match the data on the corresponding official batch records, as in the case for the amount of raw materials added to (b)(4) Suspension USP (b)(4)% Batch (b)(4). Although your firm stated that this batch was destroyed on October 18, 2013, the investigators observed that your records showed that the batch was removed from quarantine on October 25, 2013.  The use of unofficial and scratch paper records is not acceptable CGMP.  Employees interviewed during the inspection admitted that your firm recorded activities in batch records that were not performed. Specifically, your head of production reported to our investigator that he completes “in process quality assurance check” fields in the batch record but does not actually perform the listed operations. In response to this letter, describe your investigation into this situation, outlining your efforts to determine the scope of data falsification within batch records and your corrective and preventive actions. 2. Your firm failed to maintain adequate written records of major equipment maintenance (21 CFR 211.182).  two maintenance logbooks that included multiple entries describing significant equipment malfunctions, but for which no investigation into the potential effect on product quality was performed.  your records do not always include information on repairs following these malfunctions.  no maintenance actions or product impact investigations were recorded for out-of-limit findings during equipment calibration  ten serialized entries had been torn out of the logbooks. Your staff could not locate these records during the inspection and reported to our investigator that the entries had likely been destroyed.

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3. Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform his or her assigned functions (21 CFR 211.25(a)).  contract employees had not received any training on CGMP  falsified documents designed to demonstrate the effectiveness of CGMP training. 4. Your firm did not follow written procedures regarding storage and warehousing of drug products (21 CFR 211.142).  unable to locate approximately (b)(4) units of (b)(4) injection from Batch #(b)(4) that had been manufactured several weeks earlier  failed to produce packaging records for these units during the inspection. 5. Your firm failed to maintain the buildings used in the manufacture, processing, packing, or holding of a drug product in a clean and sanitary condition and keep them free of infestation by rodents, birds, insects, and other vermin (21 CFR 211.56(a)).  significant mold growth in the washroom located at the entry to the sterile manufacturing area  The ceiling of this room had been allowed to deteriorate to such an extent that it caved in  This room shares a common mezzanine with the adjacent sterile processing rooms.  numerous dead insects in the “Sample Pass Through” Room, located approximately(b)(4) from the Sterile Filling Line #(b)(4) of the small volume parenterals facility.  dead and decaying frogs were found next to the product exit dock. 6. Your firm failed to exercise strict control over labeling issued for use in drug product labeling operations (21 CFR 211.125(a)).  found numerous loose and uncontrolled labels for multiple products in the open office area adjacent to the packaging lines.  Unused labels were not stored in a manner to prevent mix-ups or mislabeling. The Compounding Shop, Inc. 8/12/14 (FLA-14-22) FDA investigators 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 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 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)]. 3. Your firm does not have, for each batch of drug product purporting to be sterile and/or pyrogen-free, an appropriate laboratory determination of satisfactory conformance to final specifications for the drug product [21 CFR 211.167(a)]. 4. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas [21 CFR 211.42(c)(10)(iv)]. 5. Your firm failed to ensure that personnel involved in the manufacture, processing, packing, or holding of drug products wear clothing appropriate to protect drug products from contamination [21 CFR 211.28(a)]. 6. Your firm does not have, for each batch of drug product, an 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/ucm410634.htm

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Zions Rx Formulations Services LLC dba Rx Formuations Serv. 8/15/14 (WL# 32-14) FDA investigators 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. The violations include, for example: 1. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)). 2. 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)). 3. Your firm does not have, for each batch of drug product purporting to be sterile and/or pyrogen-free, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product (21 CFR 211.167(a)). 4. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination (21 CFR 211.28(a)). 5. Your firm failed to establish an adequate system for maintaining equipment used to control the aseptic conditions (21 CFR 211.42(c)(10)(vi)). 6. 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/ucm410730.htm AUDIT FINDINGS - EMA Non Compliance Reports Renown Pharmaceuticals Pvt. Ltd., Gujarat, India This is the first time this site has been inspected by EEA- inspectorate; it was inspected in relation to a marketing authorization application currently under assessment by HPRA (Ireland). Batch release site for the EU is located in Spain. Several critical and major deficiencies to EU Good Manufacturing Practice Guide (Part I) were observed. Most serious deficiencies are summarized below: • Defective performance of cleaning, lack of effective supervision of cleaning and housekeeping. • Inappropriate validation of cleaning procedures. • Failures in line clearance • Record integrity and veracity: some records were made up or altered. • Defects on deviation recording and investigation. • Lack of mechanisms to ensure integrity of analytical data.

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VETPROM AD, Bulgaria During last inspection on this site were found 27 deficiencies, 8 of them were rated as Major. 1. Pharmaceutical quality system of the company at this stage does not function stable, a reliable system for determining the depth of the problems and re-evaluation of quality is missing; 2. Audits of manufacturers of active substances are not carried out and there is no evidence that the active substances used in the manufacture of medicinal products are manufactured in accordance with Good Manufacturing Practice; 3. There is no evidence of the suitability of microbiological method for sterility test; 4. The procedure for cleaning validation is ineffective and does not include all medicines (human and animal medicinal use); 5. Test for component composition of Gentamicin sulphate was not carried out according to the registration dossier of the medicinal product 6. The devices for measuring critical parameters of sterilization processes are not subject to the annual plan of calibration; 7. The plan - program for re-qualification of the sterilization equipment is not executed; 8. An input is not performed to control the nitrogen that is in direct contact with the product, the certificate of the manufacturer's analysis of the nitrogen for filling and welding in an inert atmosphere of injection solutions does not meet the performance indicators of Nitrogen according to Ph. Eur. 9. Repeating discrepancies from the previous inspection : - quality of some of the excipients used is not intended for pharmaceutical purposes; - the status of HVAC is not adequately monitored and controlled.

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Guest of the Month
[PU]: What are the challenges in the development and manufacturing of API? How can we overcome these challenges?
Dr. MD: The challenges faced in the life cycle management of API are tremendous and applicable to all Innovators and Generic organizations. I would like to describe the challenges of each stages separately.
Challenges during Development: For innovator organisations, the key challenge is to identify the correct molecule. As we understand, out of thousands of new chemicals only one new chemicals turns in to drug. Although there are various tools available now a days, this area remains challenging. Once the molecule is identified, development of molecule in a stipulated timeline is a great challenge. Innovator himself cannot develop all the steps, it would consume more time. Hence dependency of CRO‟s is critical and protecting the IP (Intellectual Property) would be another challenge.
Obtaining patent also challenge. The number of steps involved in developing the molecule, conducting clinical trials, obtaining patent is a lengthy exercise and there is no surety that the molecule will remain for long as there are number of other molecules for the same treatment is available and over a period proved to be better than the original molecule. Regulations regarding development is also becoming demanding and Risk Based approach and QbD (Quality by Design) play major part in development of molecule. QbD approach is expected to help in identifying the right kind of experimentation during development and reduced number of experiments. However, due to poor understanding of the QbD requirements and there is no appropriate guideline for execution, the work load in development cycle is getting high at least in Indian Generic Scenario. In terms of Generic Organisation, for FTF (First to File) there are several players for the same molecule, hence time is a big challenge. Hence results in poor development of molecule.
Technology Absorption and Transfer: Operational Elements which may affect the quality of the products are not considered appropriately during development, coupled with Scale up issues the Technology Transfer become highly challenging. Only limited sharing of process knowledge during Technology Transfer make the life of plant personnel tougher. In real sense, the research and development in India is done in plants.
During commercial campaign: There is a huge gap persist between the validation campaign and commercial campaign, due to
Dr. M Damodharan Vice President Global Quality and Regulatory at Sai Life Sciences. Formerly Head Quality - API at Ranbaxy Laboratories Dear Dr. Damodharan, Thank you for exclusive interview for Pharma Uptoday.

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regulatory approval requirements. During this period, there are lot of change happens, in terms of equipments, people, raw materials, operation methodology etc. due to which the process stabilization takes longer time. Poor investigation of OOT/OOS also leads to difficulty. Appropriate root cause identification is a big challenge in API industry as the steps are involved has a complex chemistry, operational issues, procedural deficiencies, human errors etc. To overcome the challenges following measures are recommended: 1. Understanding of QbD concept during development stage and execute appropriate DoE to arrive at optimum level of process. 2. Technology absorption/Transfer group to be effective and appropriate fitment in the plants of the technology to be executed. 3. In depth investigation into the problem and identify exact root cause and take appropriate CAPA to avoid repeat failures. [PU]: Can you please share some major deficiencies experienced in GMP in API manufacturing? Dr. MD: In my experience following are the major deficiencies experienced in API manufacturing. 1. Poor understanding of the process at shop-floor level due to poor development of molecule and technology transfer. 2. The failure rate at various stages. This is due to poor investigations. If we analyse the failure rate in API process, most of the failures pertains to Related substances, Residual solvents and Particle size. This gives clear indication that we need to look at the crystallization, centrifugation, washing and drying. If we divide the root cause for the various category like Process, Facility (Including Equipment), Procedural and Human, most of the cases may lead to procedural deficiency. Since the appropriate root cause is not identified or we do not get into the depth of the problem, the repetition of failure happens. 3. QA Systems: Lengthy procedures. As Pharma Industry revolves on Guidelines and guidelines are always improve over a period, the understanding of the real requirement become difficult and bringing into operatable guideline/SOP is challenging. Also Training play a major part in communicating the current requirement, in which most of the organization fails. This leads to non-compliance at all levels. Make stringent procedure without understanding the real requirement and make the life of chemist/operator difficult to comply. 4. Transparency: Transparency in communication plays a major role in identifying the real problem and address it appropriately. In India, QA is seen as Police men, not as enabler. QA also needs to play a major role in setting up appropriate system based on minimum guideline and improve upon over a period. This also leads to non-compliance to the requirements. 5. Training: Training is a major concern in Indian Pharma Industry. In, most of the organization Training department is expected to complete the task rather than the real education to the people. This leads to a big non-compliance. 6. Data Integrity: Understanding on the data integrity issue is very important and essential. Based on the recent warning letters issued to Indian Pharma companies, we need to learn the current expectations and ensure there is no data integrity issue in every activity.

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[PU]: Can you share your experience related to key problems experienced during inspections of the manufacturing API? Dr. MD: For the past 3 years, I have faced toughest inspections. My experience is as under. 1. There is a shift observed in audit methodology. Earlier the auditor used to review only documents, however in the recent past the audits are done in the shop floor and the auditor are interacting only with the operators/chemists and observing the operations. 2. There is a shift from Audit to Investigation mode. 3. One to one interaction with Chemists/Operators is done by the auditors. 4. Effective monitoring of 6 quality system was also challenged. 5. 21 CFR Part 11 compliance was a focus for the past 3 years. Particularly in Quality Control. 6. Data integrity was a main focus in the recent audits. 7. As FDA increased its focus on data integrity and reliability, inspectors are examining data based on multiple regulations and standards including cGMP, GLP, GCP and AIP (Application Integrity Policy). 8. Auditors are also focusing on the resources management. 9. Effective self -inspection mechanism was also challenged. 10. Trends of failures were deeply looked in to verify the robustness of the process. 11. Training needs identification were challenged and effectiveness of training were deeply scrutinized. The training effectiveness were verified at shop floor. 12. Deviation management methodology, potential activities which may fall into deviation were looked in to the various documents and challenged. 13. CAPA effectiveness were challenged for the recurrence in the failures. 14. Review mechanism in all areas were scrutinized. 15. Auditors look at corporate governance structure and Global Corrective Action, rather than quick fix solutions. 16. Regulatory Agencies also looked at how the quality signals are understood by the management and approached the problem through management review cycle and addressed. [PU]: Can you suggest some ways to prevent data integrity issues which are observed in the Indian pharma industry in the past? Dr. MD: Data integrity is the assurance that data records are accurate, complete, intact and maintained within their original context, including their relationship to other data records. In the last three years alone, FDA has issued more than 30 warning letter and form 483 inspectional observations related to electronic records.

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The solution to avoid data integrity issues [Electronic records] are as follows • The software that is being used for the analytical/manufacturing must be compliant to 21 CFR part 11. • Appropriate controls to be established and privileges to be defined. • Administrator privileges to be given to second person other than the operating person. • Every analysis/ operations being carried out shall be accounted, a verification mechanism shall be established to monitor in case of discrepancies. • Review of audit trails in terms of activities/systems to be established and followed. • Appropriate controls in the operating system also shall be established and followed. • An incident management system with appropriate investigation shall be established and followed. • Trial injections concept shall be eradicated. • Appropriate investigation shall be carried for the invalidated data. • Concurrent documentation for the hybrid system. • A well-defined back up and restoration procedures shall be established and followed For all other type of data integrity issues following are the suggestions. • No back dating/ postdating / missing entries • No discarding data • Appropriate investigation tools usage • Appropriate resources management to be established • Concurrent entries to be made for all the activities If we analyse the current data integrity issues, the basic need for the Indian pharma industry is cultural change. In Indian culture we basically works as per the oral instructions but not documenting appropriately, Also very poor in learning new activity and innovative way of working. Hence a cultural change in our mind set and working is sought to come out from the current data integrity issues. The key word would be document everything and execute apt investigation [PU]: Is it required to validate the testing procedure for intermediate during API manufacturing? Dr. MD: Yes, we need to validate the testing procedure for Intermediates during API Manufacturing.
The methods used for API testing are to be Validated and submitted for Regulatory filings and the regulatory agencies are also not expecting to file Intermediates method validation. However off late, the regulatory agencies raise queries on the control of impurities at intermediate stage, which automatically lead to method validation of Intermediate stages. Currently, various organizations got observation for non-validation of intermediates and raw materials method of analysis also. In a nut shell, the validation of process means, not only the process parameters, yield, quality the methods used in each step to be validated.

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Regulations of the Month Subpart J--Records and Reports § 211.180 General requirements. (a) Any production, control or distribution record that is required to be maintained in compliance with this part and is specifically associated with a batch of a drug product shall be retained for at least 1 year after the expiration date of the batch or, in the case of certain OTC drug products lacking expiration dating because they meet the criteria for exemption under 211.137, 3 years after distribution of the batch. (b) Records shall be maintained for all components, drug product containers, closures, and labeling for at least 1 year after the expiration date or, in the case of certain OTC drug products lacking expiration dating because they meet the criteria for exemption under 211.137, 3 years after distribution of the last lot of drug product incorporating the component or using the container, closure, or labeling. (c) All records required under this part, or copies of such records, shall be readily available for authorized inspection during the retention period at the establishment where the activities described in such records occurred. These records or copies thereof shall be subject to photocopying or other means of reproduction as part of such inspection. Records that can be immediately retrieved from another location by computer or other electronic means shall be considered as meeting the requirements of this paragraph. (d) Records required under this part may be retained either as original records or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. Where reduction techniques, such as microfilming, are used, suitable reader and photocopying equipment shall be readily available. (e) Written records required by this part shall be maintained so that data therein can be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures. Written procedures shall be established and followed for such evaluations and shall include provisions for: (1) A review of a representative number of batches, whether approved or rejected, and, where applicable, records associated with the batch. (2) A review of complaints, recalls, returned or salvaged drug products, and investigations conducted under 211.192 for each drug product. (f) Procedures shall be established to assure that the responsible officials of the firm, if they are not personally involved in or immediately aware of such actions, are notified in writing of any investigations conducted under 211.198, 211.204, or 211.208 of these regulations, any recalls, reports of inspectional observations issued by the Food and Drug Administration, or any regulatory actions relating to good manufacturing practices brought by the Food and Drug Administration.

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§ 211.182 Equipment cleaning and use log.
 A written record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and adjustments), and use shall be included in individual equipment logs that show the date, time, product, and lot number of each batch processed.
 If equipment is dedicated to manufacture of one product, then individual equipment logs are not required, provided that lots or batches of such product follow in numerical order and are manufactured in numerical sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use shall be part of the batch record.
 The persons performing and double-checking the cleaning and maintenance (or, if the cleaning and maintenance is performed using automated equipment under 211.68, just the person verifying the cleaning and maintenance done by the automated equipment) shall date and sign or initial the log indicating that the work was performed.
 Entries in the log shall be in chronological order.
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