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Pharma Uptoday Monthly Magazine Volume 8 issue Nov 2014

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To recap the previous month's pharma highlights to Pharma Uptoday members, Monthly magazine Volume 8 has been released with the following content.

3 News Uptoday

14 New Guidance

30 Audit Findings

483 Observations

- Exemplar Lab, MA

- Genentech Inc

- Celltex Therapeutics Corporation

- APP Pharmaceuticals, LLC

- Reganeron Pharmaceuticals, Inc.

Warning Letters

- Hospira, Austarlia

- Sanjiu Medical and Pharmaceutical Co.,

- Beacon Hill Medical Pharmacy

EMA Non-Compliance Reports

- Wockhardt Limited, Nani Daman

- Fujian South Pharmaceutical, China

40 Regulations of the Month

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

§ 211.186 Master production and control records

Published in: Healthcare
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Pharma Uptoday Monthly Magazine Volume 8 issue Nov 2014

  1. 1. VOLUME: 8 - ISSUE: NOV 2014 | PHARMA UPTODAY For feedback, suggestions & queries write to us on “pharmauptoday@gmail.com” To subscribe free online pharma newsletter write a mail to “pharmauptoday@gmail.com” with subject “Add mail”.
  2. 2. PHARMA UPTODAY 2 Inside this issue 3 News Uptoday 14 New Guidance 30 Audit Findings 483 Observations - Exemplar Lab, MA - Genentech Inc - Celltex Therapeutics Corporation - APP Pharmaceuticals, LLC - Reganeron Pharmaceuticals, Inc. Warning Letters - Hospira, Austarlia - Sanjiu Medical and Pharmaceutical Co., - Beacon Hill Medical Pharmacy EMA Non-Compliance Reports - Wockhardt Limited, Nani Daman - Fujian South Pharmaceutical, China 40 Regulations of the Month §211.184 Component, drug product container, closure, and labeling records § 211.186 Master production and control records
  3. 3. PHARMA UPTODAY 3 News Uptoday GDUFA Information Technology/Informatics Plan FY 2013 – FY 2017 FDA publishes GDUFA Information Technology/Informatics Plan FY 2013 – FY 2017. This 5-year plan describes how the Food and Drug Administration (FDA) proposes to meet the information technology (IT) goals of the Generic Drug User Fee Act Amendments of 2012 (GDUFA), section 744G of the Food, Drug, and Cosmetic Act (FD&C Act) Authorization Program Performance Goals and Procedures for fiscal years (FY) 2013 through 2017. The plan includes FDA’s proposed approach for enhancing business processes, data quality and consistency, supporting technologies, and IT operations. Industry can use this information to adequately plan for, resource, and implement the necessary IT changes to enable efficient and consistent adoption of the data standardization, IT, and informatics changes described in the GDUFA Program Performance Goals and Procedures for FY 2013 through FY 2017. Indian firm, 26 others cited for failing to pay GDUFA fees Indian generic manufacturer Marck Biosciences has received a warning letter from the US FDA for failing to pay its annual facility fees for the past two years, which for foreign fixed-dose formulation facilities in 2014 was $235,152 The warning letter noted that the facility was identified in a pending and/or approved ANDA (Abbreviated New Drug Application) on the dates for self-identification for FY 2013 and 2014. “The facility has self-identified for 2013 and 2014 but, has not paid the 2013 or 2014 facility fees as required by GDUFA [Generic Drug User Fee Amendment]. Therefore, all finished dosage forms of drugs or APIs, as well as drug containing an API, manufactured at the facility are misbranded,” the FDA warned. But the problems for Marck Biosciences extend beyond their failure to pay the facility fees. The firm was cited in a warning letter in August for data falsification and unsanitary conditions . Marck did not respond to a request for comment. Other Firms Germany-based CMO CPM Contract Pharma in 2013 became the first firm to receive a warning letterfor failing to pay a facility fee. Twenty-seven firms are included on this year’s arrears list for GDUFA facilities. Meanwhile, 20 other firms, including Pfizer, Bristol-Myers Squibb and AstraZeneca are included in a list of companies with outstanding facility fees. Only facilities that manufacture positron emission tomography drugs are exempted from the facility fee and other GDUFA fee requirements.
  4. 4. PHARMA UPTODAY 4 Foreign generic firms saw a more than $40,000 increase in facility fees in 2014 when compared with the fees for 2013. MHRA launches Composite co-ordinated collections (CCC) – National pilot scheme MHRA launches a scheme for co-ordinating the submission and assessment of multiple parallel variations to marketing authorisations which impact on the SmPC and changes to the packaging/patient information leaflet. The scheme is called Composite Co-ordinated Collection (CCC) and effectively ring- fences multiple applications to streamline processing. CCC results from the MHRA’s Red Tape Challenge and has the benefit of requiring only one consolidated label/leaflet mock-up to be submitted. MHRA is making more widely available a new scheme for coordinating the submission and assessment of variations and changes to the packaging/patient information leaflet that are submitted in parallel to amend a marketing authorisation. The scheme is called Composite Co-ordinated Collections (CCC) and is being piloted from October 2014. The benefits of the CCC scheme for multiple parallel procedures are that:  processing and assessment of applications will be coordinated and more streamlined  only one consolidated mock-up needs to be submitted  the normal rules of grouping and bulking of variations apply  the scheme costs no more than current submissions This diagram sets out how the CCC scheme works:
  5. 5. PHARMA UPTODAY 5 Each CCC application can be made up of a mixture of variations (comprising single or grouped changes) and Article 61(3) applications to amend labels and patient information leaflets. The CCC can be applied to one or more product licences. All the applications are ring-fenced, effectively providing a one-stop- shop for updating for updating product information (SmPC, PIL and labelling). The CCC scheme excludes purely Type IA notification and notifications of changes to packaging, patient information leaflet and labelling under the self-certification scheme. Urgent or significant variations that impact on the safety of a product should not be submitted through the CCC scheme, as it may delay implementation of the changes. Federal judge approves FDA consent decree with Ascend Laboratorie A federal judge from the U.S. District Court for the Southern District of Ohio entered a consent decree for permanent injunction against Ascend Laboratories, LLC, of Montvale, New Jersey on Oct. 10. The U.S. Department of Justice filed the consent decree on behalf of the U.S. Food and Drug Administration. The consent decree requires Ascend Laboratories to post bond for the release of their unapproved drug products seized by U.S. Marshals in May 2014, which the company is then responsible for destroying under the FDA’s supervision. The drugs were seized at a warehouse in Cincinnati operated by Masters Pharmaceutical, Inc. (doing business as RXTPL). In addition, the consent decree prohibits Ascend Laboratories and all other associated persons who act in concert with the company from manufacturing and distributing unapproved drugs until the company obtains FDA approval, including: Pramoxine-HC Otic Drops; Hydrocortisone Acetate Suppositories 25 milligrams; Urea Cream 39%; Urea Cream 40%; and Urea Lotion 40%. “Manufacturing and distributing unapproved prescription drugs puts patients’ health at risk since they have not been found to be safe, effective or made using quality manufacturing practices,” said Ilisa Bernstein, acting director of the Office of Compliance in the FDA’s Center for Drug Evaluation and Research. “Companies that fall short of our requirements risk FDA action to stop the distribution of their products.” The FDA inspected Ascend Laboratories’ New Jersey facility in November 2013 and Masters Pharmaceutical’s Cincinnati warehouse in February 2014. The inspections revealed that Ascend Laboratories was marketing drug products without FDA approval and adequate directions for use. The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation's food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
  6. 6. PHARMA UPTODAY 6 Indian drugmakers scramble to prevent shortages of HIV/AIDS meds Some Indian companies that had put off production of HIV/AIDS meds while they waited for the government to sign contracts are now having to seriously ramp up because of shortages of some meds, Reuters reports. Aurobindo Pharma is among those and expects to supply 2.4 million tablets by the end of October, a senior executive told the news service. The National AIDS Control Organization website says that India needs 7.2 million tablets a month to meet demand, and Reuters says that as many as 150,000 patients risk going without meds this month because bureaucratic delays mired the process. India's Ranbaxy to pay $40 million to settle Texas Medicaid pricing litigation Indian generic drugmaker Ranbaxy Laboratories Ltd said it has agreed to pay $39.75 million to settle litigation concerning its participation in Texas Medicaid, the U.S. federal-state healthcare program for people with low incomes. The litigation related to the manner in which Ranbaxy historically reported pricing data to Texas Medicaid for some drugs, Ranbaxy said in a statement on Thursday. The payments will be made in tranches through August 2015, it said. Ranbaxy in May said, without elaborating, it had made a provision of 2.38 billion rupees ($38.57 million) in its first quarter results for "certain settlements done with the government authorities" in the United States. Last month, the company said U.S. federal authorities had sought details on how it reported pricing data for some products eligible for reimbursement under Medicaid. Analysts on Thursday said they did not expect any future impact on Ranbaxy's earnings from the Texas settlement, citing the provision. The company, which is in the process of being acquired by larger rival Sun Pharmaceutical Industries Ltd, said it "believes it fully complied with all the relevant laws." Ranbaxy's Texas settlement comes after the company pleaded guilty last year to felony charges relating to drug safety. It agreed to pay $500 million in civil and criminal fines under a settlement agreed with the Department of Justice. New EMA's Reflection Paper on API Starting Materials According to the Guideline ICH Q11 "Development and Manufacture of Drug Substances (chemical entities and biotechnological/biological entities", the chemical substance must be defined in the early drug product development phase which is used as the starting material for the manufacture of the API. This "Starting Material" marks the point in the route of synthesis where GMP conditions
  7. 7. PHARMA UPTODAY 7 have to be applied. According to ICH Q11, the criterion for the definition of a starting material is its molecular structure and it should already contain a significant structural element of the subsequent API. Yet, the further statements in Chapter 5 of the ICH Q11 Guideline on starting materials aren't so straightforward and have led to misunderstandings and misinterpretations in the months following the publication of the guideline. Disagreements between applicants and the assessors of the regulatory authorities processing the applications are rather almost the rule. This situation drove the EMA to release a document entitled "Reflection paper in the requirements for selection and justification of starting materials for the manufature of chemical active substances". The paper was published on 10 October 2014 on the website of the Agency and aims to clarify the selection of starting materials for synthetic and semi-synthetic APIs as well as the justification of such a selection. Within in total 11 so-called "explanatory notes" the Agency presents its expectations from the applicants regarding the information about an API starting material in a marketing authorisation application. Find below some examples:  The route of synthesis indicated should include so many synthesis steps to clearly and unambiguously follow the formation of the efficient principle of the API. Short synthetic routes related to the argument that the efficient structural element in the molecule is already available won't normally be accepted.  A detailed description is required of how the quality-relevant synthesis steps are controlled.  All the principles described for synthetic starting materials also apply to semi-synthetic starting materials.  Changes to the synthetic route should always be assessed for their impact on the quality of the active substance.  A statement that a starting material is commercially available isn't sufficient to justify its selection. The future will show to what extent EMA's document contributes to the clarification of misunderstandings between applicants and regulatory authorities. USP's New Requirements for Compendial Validation An interesting article from the USP on the future requirements for compendial validation has been published in the Pharmacopoeial Forum 39(6). This is the first General Chapter in a series of chapters which should introduce significant changes in the approaches to validation and its influences on compendial procedures.
  8. 8. PHARMA UPTODAY 8 This new chapter <1200> will concentrate on the types of data expected by the USP to see if an analytical method can be accepted before it is included in USP/NF. Methods containing the data expected in the future will be suitable for compendial applications. According to USP's "General Notices" 6.30, alternative procedures may be used as long as they have been validated or have been demonstrated to be equivalent to or better than the existing compendial procedure. The article lists the different parameters for compendial validation. Concrete propositions are made. Five standardised studies may be used to evaluate the acceptability of a new procedure:  Specificity  Accuracy  Precision  Range  Detectability The USP wishes to get feedback to the propositions made in this article. System Suitability for USP Chromatographic Methods An interesting article from the USP experts group "Small Molecules" has been published in the Pharmacopoeial Forum 39(5). It deals with USP's future requirements regarding system suitability tests (SST). SSTs are performed each time an analytical method is used. Together with instruments qualification and methods validation, the SST ensures the quality of analytical test results. The SST shows that a procedure and an instrumental system are performing as they did when the procedure was validated and that the method is thus "fit for purpose" for the intended use. General requirements can be found in the USP Chapter <621> Chromatography which also contains provisions and acceptance criteria for individual parameters of the SST. Nevertheless, parameters and acceptance criteria laid down in specific monographs always take priority over the general provisions provided in General Chapter <621>. In the article, the USP Expert Committee has noted that because of many different sponsors who have submitted a number of various monographs to the USP, inconsistencies with regard to SSTs in the USP have arisen. That's why the USP Expert Committee has described in this article which data are required on SSTs for new monographs or monographs to be updated. The following descriptions are provided:
  9. 9. PHARMA UPTODAY 9  Assay  Impurities  Dissolution  Content Uniformity New MAPP Foreign Language Labeling  This MAPP outlines the policies and procedures for Center for Drug Evaluation and Research (CDER) staff when applicants submit new drug applications, biologics license applications, abbreviated new drug applications, or supplemental applications that contain labels and/or labeling in a foreign language intended for distribution in the United States and/or its Territories.  This MAPP pertains to the following types of labeling: labels, prescribing information (also called package insert), patient package inserts, instructions for use, and Medication Guides. CDER Small Business and Industry Education Series FDA releases "Engaging with the FDA During New Drug Development" webinar in the website. For more details click the link below. http://www.accessdata.fda.gov/cder/sb-navigate/index.htm MAPP on "CDER Co-Sponsorship Agreements for Events" The purpose of this MAPP is to ensure consistency and continuity across CDER as the Center engages in not-for-profit events (e.g., conferences, meetings, symposia, webinars, and workshops) co-sponsored with outside non-Federal organizations that provide relevant expertise and share a mutual interest and benefit in the subject matter. Pursuant to this MAPP, a network of CDER Co-Sponsorship Coordinators will be established to manage CDER co-sponsorships with outside organizations. MAPP on "CDER System of Record" This MAPP documents CDER’s System of Record (SOR) and outlines the policies and procedures for its governance. This includes the following:  Definition of a Record and SOR  Identification of the various systems within CDER that holds the SOR  Listing of the SOR attributes for the identified CDER systems EMA encourages companies to submit quality type I variations for 2014 by end of November
  10. 10. PHARMA UPTODAY 10 The European Medicines Agency (EMA) is advising marketing authorisation holders to submit any type IAIN and type IA variations for 2014 by Friday 28 November wherever possible. This will enable the Agency to acknowledge the validity of the submissions before the Agency's closure between 24 December 2014 and 2 January 2015 within the 30-day timeframe set out in Article 14 of Commission Regulation (EC) No 1234/2008. Marketing authorisation holders intending to submit type IB variations or groupings of type IBs and type IAs in December 2014 should liaise with the EMA prior to submission. An email should be sent to: IBquery@ema.europa.eu indicating in the subject line: “Type IB December Submission” and mentioning in the body of the email the name of the product, the intended submission date and the scope(s) to be applied according to the Classification guideline. Type I variations are minor changes to the marketing authorisation of a medicine. Type IAIN and IA variations have no impact on the quality, safety or efficacy of the medicine. Type IAIN variations must be notified to the national competent authority or the EMA immediately following implementation, in order to ensure the continuous supervision of the medicine. Type IA variations do not require immediate notification and should be notified to the national competent authority or the EMA within 12 months of implementation, or earlier in certain cases. Type IB variations must be notified to the national competent authority or the EMA before implementation, but do not require a formal approval. Upon acknowledgement of receipt of a valid notification, the marketing authorisation holder must wait for a period of 30 days to ensure that the notification is deemed acceptable by the national competent authority or the EMA before implementing the change. Source: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/10/news _detail_002198.jsp&mid=WC0b01ac058004d5c1 FDA Launches Webpage for its Drug Quality Samplling and Testing Programs Drug Quality: Postmarket Sampling and Testing FDA's requirements for approval of new andgeneric drugs and biologics are among the highest standards across the globe. Prior to FDA approval, the manufacturer must prove the product is safe, effective, and high quality. To help assure safe and effective drugs are sold in the United States, we test selected drugs in FDA laboratories and through research contracts and grants. This includes active pharmaceutical ingredients (API) used to make the product and the finished drug product sold to consumers. We test using the same standards that are part of the drug approval process for identity, strength, purity, and bioavailability, which is also used to establish bioequivalence.
  11. 11. PHARMA UPTODAY 11 We are committed to protecting patients from potentially unsafe, non-effective or poor-quality drugs. Postmarket testing is one way that FDA works to help ensure patients have access to safe, effective, quality drugs. Source: http://www.fda.gov/Drugs/ScienceResearch/ucm407277.htm#collapseTwo First-Time Generic Drug Approvals - October 2014 Generic Drug Name Generic Manufacturer Brand Name Tentative Approval Date Approval Date 1 OLOPATADINE HYDROCHLORIDE NASAL SOLUTION (NASAL SPRAY), 665 MCG/SPRAY APOTEX INC. PATANASE NASAL SPRAY 10/8/2014 2 IVERMECTIN TABLETS USP, 3 MG EDENBRIDGE PHARMACEUTICALS, LLC STROMECTOL TABLETS 10/24/2014 India relies on China for 90 per cent of drug raw materials Imagine a situation where an Indian soldier's medical kit is running out of essential drugs on a battle front. This may sound like a figment of imagination, but given India's acute dependence on China for key ingredients (active pharma ingredients) for several essential drugs including several antibiotics, the prospect of such a scenario isn't all that remote. India depends heavily on imports — over 90% — from China for many key raw materials (mostly intermediates and some active pharma ingredients) that go into the making of at least 15-odd essential drugs, reckons a Boston Consulting Group (BCG) and Confederation of Indian Industry (CII) report reviewed. "Any deterioration in relationship with China can potentially result in severe shortages in the supply of essential drugs to the country. Additionally, China could easily increase prices of some of these drugs where it enjoys virtual monopoly," said Bart Janssens, partner, BCG. These drugs include the most commonly used painkiller such as paracetamol, Aspirin; antibiotics such as
  12. 12. PHARMA UPTODAY 12 Amoxicillin and Ampicillin, Cephalexin, Cefaclor, Ciprofloxacin, Ofloxacin, Levofloxacin; first line diabetes drug Metformin; antacid Ranitidine. There are no domestic producers left for many of these such as Penicillin-G, and its derivative 6- Aminopenicillanic acid, or 6-APA, as it is commonly known, making the country entirely dependent on imports for key intermediates used in many essential antibiotics, including semi-synthetic penicillins and semi-synthetic cephalosporins. The report which the CII and BCG have shared with the government * underlines the risks of such over- dependence on China for critical raw material and commonly used drugs. Any supply risk, in terms of shortage of these advanced intermediates, would endanger the production of APIs and bring the manufacturing of critical drugs to a halt, putting the health of a large proportion of the * total population at risk, he added. Source: http://economictimes.indiatimes.com
  13. 13. PHARMA UPTODAY 13 Conformity, Conformance or Compliance? Do you say conformity or compliance? Is it okay to use conformance instead of conformity? Does it matter? The ISO 9000:2000 Fundamentals and Vocabulary standard defines conformity as the fulfillment of a requirement. A note says conformance is synonymous, but deprecated (meaning use of that term is considered obsolete). ISO 9000 defines nonconformity as the non-fulfillment of a requirement. It doesn’t define compliance. Although QS-9000 doesn’t define conformity, it does define nonconformity as a “process” which does not conform to a quality system requirement. It makes the distinction that a nonconformance is a “product or material” which does not conform to customer requirements or specifications. So, QS-9000 uses both conformity (process) and conformance (product). However, ISO 9000 uses conformity as fulfilling either process or product requirements. ISO/TS 16949:2002 (the replacement for QS-9000 by 2006) uses the ISO 9000:2000 definitions for conformity and nonconformity. It dropped the QS-9000 use of nonconformance. TL 9000 Release 3.0 refers to the ISO 9000:2000 definitions for conformity and nonconformity. The Release 2.5 definition of compliance has been dropped. The prior release defined compliance as an affirmative indication or judgment that a product has met the requirements of the relevant specifications, contract or regulation; also the state of meeting the requirements. ISO/IEC Guide 2:1996 defines conformity as “fulfillment by a product, process, or service of specified requirements”. The American Heritage Dictionary defines conformity as acting or behaving in accordance with socially accepted standards, conventions, rules, or laws. It defines compliance as the disposition or tendency to yield to the will of others. Conformity can be viewed as internally driven, such as our voluntary, consensus- based standards. Compliance can be viewed as externally imposed. So, we should use conformity, not conformance or compliance, when referring to fulfilling product and process requirements. Of course, if customers impose conformity to ISO 9001, your organization may feel like it has to comply rather than conform.
  14. 14. PHARMA UPTODAY 14 New Guidance New EU-GMP Chapter 8 Published: COMPLAINTS AND RECALLS The European Commission has published the final Chapter 8 of the EU Guidelines for GMP (Complaints, Quality Defects and Product Recalls). The chapter has been amended completely and hence providing a completely new chapter compared to the current version that addresses only Complaints & Recalls.'Pervasive changes have been made to this Chapter which now reflect that Quality Risk Management principles should be applied when investigating quality defects or complaints and when making decisions in relation to product recalls or other risk-mitigating actions' EU says. The revised version formalizes the expectations for: • Personnel and Organization • Procedures for handling and investigating complaints including possible quality defects • Investigation and Decision Making • Root Cause Analysis and Corrective and Preventative Actions • Product Recalls and other potential risk-reducing actions The new version of Chapter 8 requires the implementation of Quality Risk Management principles and appropriate root cause analysis when investigating quality defects and complaints. The scope covers Complaints, Quality Defects (a new concept in the revision) and Recall issues with respect to marketed medicinal products and investigational medicinal products (IMPs) that have been released to clinical trials. The revised chapter details the explicit requirements for written procedures like SOPs. They should at least address the following: • The description of the reported quality defect. • The determination of the extent of the quality defect. • Handling of samples • The assessment of the risk(s) posed by the quality defect. • How decisions and assessments are made • Notification to the relevant authorities and other internal and external communications • Root cause analysis and CAPAs. The role of the Qualified Person (QP) in the certification for release of the concerned product is also emphasized. When it comes to product recalls, the new chapter also addresses risk diminution and risk-based
  15. 15. PHARMA UPTODAY 15 thinking into the recall decision-making process.In this context, the Manufacturer and Marketing Authorization Holder shall ensure continuity of supply for critical medicinal products where alternative products may not be readily available. This revision also provides further clarity with respect to Mock Recalls. Overall, the goal is to achieve information-based and scientific decisions in relation to risk-mitigating actions. However all likely causes should be comprehensively investigated leading to more adequate preventative actions being identified and put in place. Deadline for coming into operation: 1 March 2015. Draft guideline on regulatory acceptance of 3R (Replacement, Reduction, Refinement) testing approaches In accordance with Directive 2010/63/EU, the principle of the 3Rs (Replacement, Reduction and Refinement) needs to be considered when selecting testing approaches to be used for regulatory testing of human and veterinary medicinal products. A general overview is provided on animal use and current or future implementation of 3R testing approaches for quality, non-clinical (human) and safety and efficacy (veterinary) testing. WHO publishes second Draft on the Revision of its Process Validation Guideline In April 2014 WHO published a first draft to revise their Non-sterile Process Validation Guideline. Comments to the first draft from April 2014 have now flowed into the second one. This is obvious at one point or another. The table of contents and the scope have remained unchanged. Yet, the definition of process validation contains the life-cycle approach in the glossary already. Compared to the first draft, the new version now also explains the matrix approach or bracketing. Still, the introduction mentions different possibilities for process validation (traditional vs. life-cycle approach vs. hybrid). A flow diagram "may" be helpful. At the end of the introduction, a flow diagram intends to illustrate the process validation life-cycle. Now, the diagram mentions "validate process" already at the process design stage. The chapter on process design contains no major changes compared to the first draft.
  16. 16. PHARMA UPTODAY 16 In the chapter "process qualification", a risk assessment is required for the change in batch size from scale up to commercial batch size. Explicitly, manufacturers are requested to implement the new validation approach. However, it is mentioned that full implementation may take time. In the interim, the traditional approach or concurrent validation may be accepted. Also a hybrid approach (based on a scientific basis and risk management principles) may be an alternative. Compared to the first draft, the chapters "continued process verification" and "change control" haven't changed significantly. Conclusion: The second draft is considerably more stringent than the first one. The document is a bit of a mix of FDA's Guidance on process validation and EMA's process validation guideline where the terms used come from the FDA Guidance. Both documents are also listed under references. A few inconsistencies remain. The topics risk assessments, QRM, and risk-based approaches are seen in very different ways in the document. The chapter "background and scope" recommends a risk-based approach. Risk assessments are referred to as "should" requirements, QRM rather as "nice to have" ("when applying QRM..."). A flow diagram shouldn't be only named as "may" requirement. Naming process validation under process design in the flow diagram for the process validation life-cycle (background/objective) is against the definition in the glossary according to which process validation include the whole life-cycle. Moreover, mentioning concurrent validation as an alternative to the life- cycle approach could be misunderstood. It is astonishing that ICH Q10 hasn't been referred to although some elements of this document (e.g. continuous improvement, product life cycle) have been used. Saudi Food and Drug Authority publishes Drug Master File Guidance This year in August, the regulatory authority of Saudi Arabia published a guideline entitled "Drug Master File (DMF): Guidance for Submission". The document describes the formal prerequisites to be fulfilled to ensure the successful submission of a DMF. The following elements have to be part of a DMF:  Cover letter - This letter shall include all technical-formal information like for example the name of the API, trade name, name and address of both the manufacturer and the DMF holder, registration or reference number.  Letter of access: authorisation to review and reference the DMF. The same information as in the cover letter should also be indicated here. If the API is manufactured at different manufacturing sites, all sites have to be listed.
  17. 17. PHARMA UPTODAY 17  Formal requirements for the DMF: the DMF must be written either in English or Arabic. Only one electronic-based copy - a CD - should be submitted. If the data volume exceeds 750 MB, a DVD should be used. In the context of this DMF Guideline, there is another important document entitled "Guidance for Submission" published by the SFDA in March 2014 in the updated version 4.0. The document contains further technical details about the storage media to be used for all submissions made to the SFDA, e.g. security requirements, password and virus protection, etc. These requirements should also be considered for the submission of Drug Master Files. Further regulations and guidelines of the Saudi Authority relevant for authorisation can be found on the website of the SFDA. WHO publishes New Version of Guide regarding the Principles of GMP The draft for comment of this super-ordinated Guideline was already published in the middle of 2013. Since then, nothing has fundamentally changed. Only changes to the following chapters have been made: 1. Pharmaceutical quality system (formerly "quality assurance") 2. Good Manufacturing practices for pharmaceutical products 7. Contract production, analysis and other activities 17. Good practices in quality control Compared to the draft from 2013, the new document contains an extended description of the pharmaceutical quality system. In Chapter 1, the ultimate responsibility of senior management has been strongly emphasized. Likewise, the aspect of qualification has been complemented. In Chapter 2, the required review of processes has been extended to the scientific aspect (so far only review based on experience only). The Guideline "Good Manufacturing Practices for Pharmaceutical Products: Main Principles" has been published as Annex 2 of the Technical Report 986. FDA releases Guideline on Critical Path Innovation Meetings This guidance describes the purpose, scope, documentation, and administrative procedures for a Critical Path Innovation Meeting (CPIM), including how to request such a meeting. The CPIM is a means by which the Center for Drug Evaluation and Research (CDER or we) and investigators from industry, academia, patient advocacy groups, and government can communicate to improve efficiency and success in drug development. The goals of the CPIM are to discuss a methodology or technology proposed by the meeting requester and for CDER to provide general advice on how this methodology or technology might enhance drug development. CDER will identify some of the larger gaps in existing
  18. 18. PHARMA UPTODAY 18 knowledge that requesters might consider addressing in the course of their work. The discussions and background information submitted through the CPIM are nonbinding on both FDA and CPIM requesters. FDA releases Guideline on The Effect of Section 585 of the FD&C Act on Drug Product Tracing and Wholesale Drug Distributor and Third-Party Logistics Provider Licensing Standards and Requirements; Questions and Answers The Food and Drug Administration (FDA) is issuing these questions and answers to assist industry and State and local governments in understanding the effects of section 585 (Uniform National Policy) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) added by Title II of the Drug Quality and Security Act (DQSA), which was enacted on November 27, 2013. Title II, which is also referred to as the Drug Supply Chain Security Act (DSCSA), establishes a Federal system for tracing prescription drug products through the pharmaceutical distribution supply chain and requires trading partners to pass, receive, and maintain certain product and distribution information. The DSCSA also requires FDA to establish Federal standards for licensing of wholesale drug distributors and third party logistics providers; the Agency is currently drafting these regulations. Section 585 sets forth a uniform national policy preempting States from establishing or continuing in effect certain standards and requirements. FDA releases Guidance for Industry : New Chemical Entity Exclusivity Determinations for Certain Fixed-Combination Drug Products The Food and Drug Administration (FDA or the Agency) is issuing this guidance to set forth a change in the Agency’s interpretation of the 5-year new chemical entity (NCE) exclusivity provisions as they apply to certain fixed-combination drug products (fixed-combinations). Historically, FDA has interpreted these provisions such that a fixed-combination was ineligible for 5-year NCE exclusivity if it contained a previously approved active moiety, even if the product also contained a new active moiety (i.e., an active moiety that the Agency had not previously approved). The Agency recognizes that fixed- combinations have become increasingly prevalent in certain therapeutic areas (including cancer, cardiovascular, and infectious disease) and that these products play an important role in optimizing adherence to dosing regimens and improving patient outcomes. As further discussed below, we are therefore revising our historical interpretation of the 5-year NCE exclusivity provisions to further incentivize the development of certain fixed-combination products. Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM38 6685.pdf
  19. 19. PHARMA UPTODAY 19 Final Concept Paper ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Life ICH has just published a Final Concept Paper for a new ICH Q12 guideline: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle. Currently, there is a lack of a harmonised approach to technical and regulatory considerations for the lifecycle management of pharmaceutical products. Although there are concepts in ICH Q8, Q9, Q10 and Q11 for a more science and risk-based approach for assessing changes across the lifecycle, several gaps exist which hinder a full realization of the benefits intended. The original aim of 'operational flexibility' in post-approval changes has not been achieved yet. The main focus at ICH to date is on early stages of the product lifecycle, especially on development and launch. A similar focus is now needed for the commercial manufacturing phase in order to fill these gaps. Furthermore, there is an inconsistent utilization of post-approval change management plans and comparability protocols. The pharmaceutical industry needs a more strategic manner to prospectively manage future changes. The proposed ICH Q12 Guideline is intended to work with ICH Q8 to Q11 Guidelines and will provide a framework to facilitate the management of post-approval Chemistry, Manufacturing and Controls (CMC) changes in a more predictable and efficient manner across the product lifecycle. This guideline will promote innovation and continual improvement, and will allow regulators (assessors and inspectors) to better understand post-approval CMC changes. The new ICH Q12 guideline will foster a more efficient regulatory evaluation, both in review and inspection, and will address these topics:  Regulatory Dossier - Reducing the appropriate level of detail and information necessary for regulatory assessment and inspection in the dossier, - Post approval changes that facilitate continual improvement and encourage the adoption of innovative technologies.  Pharmaceutical Quality System aspects (ICH Q10) - A risk-based change management system for changes, - Need for a knowledge management system over the product lifecycle.  Post-Approval Change Management Plans and Protocols - Concept of a post-approval management plan including the assessment by regulatory authorities (assessors and inspectors) - Enhanced product development and control strategy approaches (Quality by Design (QbD) providing opportunities for scientific and risk based foundations for post-approval change management plans).
  20. 20. PHARMA UPTODAY 20 This lifecycle management guidance will also support the implementation of innovative technologies such as Process Analytical Technology (PAT) and Continuous Manufacturing, and will also facilitate "operational flexibility". EDQM issues draft guidelines on endotoxins, pyrogens & sterile products, seeks comments from industry European Directorate for the Quality of Medicines (EDQM) has issued the draft guidelines on endotoxins, pyrogens and sterile products. The Pharma Europa (Ph.Eur.) which is a free online EDQM publication now seeks comments from the pharma and biotech industry on the draft guidelines. With the development of biological drugs gaining momentum, the revised draft guidelines are seen crucial for bio-pharmaceutical industry. Endotoxins from gram-negative bacteria are the most common cause of toxic reactions resulting from contamination of pharmaceutical products with pyrogens. A new section is included for the bacterial endotoxins. It covers aspects that need to be considered when establishing an endotoxin limit for a specific substance. In the case of pyrogens, the draft norms have highlighted monocyte-activation test as a potential replacement which avoids use of live animals. The regulator stated that the revision was in line with the European Convention for the Protection of Vertebrate Animals used for experimental and other scientific purposes. The test consists of measuring the rise in body temperature evoked in rabbits by intravenous injection of the substance to be examined. With reference to the new norms on sterile products, there is extensive revision. These include omission of reference to GMP. In the section on sterility assurance level, the reference to exponential inactivation has been removed as membrane filtration is not a first order process. The sections on the different sterilisation processes, now insist on the same format of equipment, sterilisation cycle, cycle effectiveness and routine control. Modern concepts for validation of steam sterilisation have been added. A wider description of the equipment suitable for dry heat sterilisation has been provided. In the section on ionising radiation sterilisation, the reference to European notes for guidance has been removed. In the section on gas sterilisation, two different types of agents are defined. These are alkylating agents and oxidising agents. In fact, the establishment of the cycle effectiveness has been described in greater detail. Under membrane filtration, the description of the microbial challenge test has been removed as it is
  21. 21. PHARMA UPTODAY 21 proposed for inclusion in the revised chapter on biological indicators. With regards to Aseptic preparation, freeze-drying under aseptic conditions is added. The regulatory authority noted that sterility is the absence of viable micro-organisms and is therefore a critical quality attribute for a wide variety of human and veterinary preparations. The drugs are not restricted to preparations administered to normally sterile areas of the body, such as parenteral and ophthalmic preparations but also covered some irrigation and inhalation preparations, intra-mammary and intra-uterine preparations, mandating stringent norms to ensure quality standards and patient safety. According to Kaushik Desai, Hon. General Secretary, Indian Pharmaceutical Association, the revision of norms was required as the biological drug development and manufacture is more robust. This has led to the creation of a stringent regulatory environment bringing about the need to update existing guidelines related to critical aspects to test biological. Therefore industry should take cognizance of the change and start implementing and also provide comments to those aspects of the guidelines which would be difficult to comply. EDQM revises 5.1.10. Guidelines for using the Test for Bacterial Endotoxins In September, the European Directorate for the Quality of Medicines & HealthCare (EDQM) published in Pharmeuropa online the information about their new policy for bacterial Endotoxins, which was approved by the Ph. Eur. Commission at its 149th Session in June 2014. Amongst others they announced for existing monographs: "BET specifications are kept in individual monographs for substances for pharmaceutical use. Existing limits remain in individual monographs to maintain the use of well-established limits. In order for the policy to be applied, the following changes are proposed to existing Ph. Eur. texts:  General chapter 5.1.10 is expanded with further considerations regarding the setting up of limits.  General monograph Substances for pharmaceutical use" In consequence it is up to the users of these EP chapters to determine whether compliance to BET is needed or not for a given substance. Where a test is included in the monograph with no specific limit, it is up to the user to set the limit for the substance, based on the following considerations: use of the substance (route of administration, patient population); calculation according to the formula given in general chapter 5.1.10; process capability; or any other considerations raised by the competent authority. Recently, on 26 September, a revision of Chapter "5.1.10. Guidelines for Using the Test for Bacterial Endotoxins" was issued and open for comments until 31 December 2014. The revision now includes
  22. 22. PHARMA UPTODAY 22 possible alternative methods to the Limulus amoebocyte lysate (LAL) test, like testing with recombinant factor C. Following a short overview of the additions and changes:  "The monocyte-activation test (2.6.30) is a suitable method to be used to rule out the presence of non-endotoxin pyrogens in substances or products."  "Hence, the analyst who wishes to implement a test for bacterial endotoxins or to replace the pyrogen test by a test for bacterial endotoxins has to demonstrate that a valid test can be carried out on the substance or product concerned; this may entail a procedure for removing interference"  "Replacement of the rabbit pyrogen test required in a pharmacopoeial monograph by an amoebocyte lysate test, or by other methods such as the monocyte-activation test or a test using recombinant factor C as a replacement for the amoebocyte lysate, constitutes the use of an alternative method of analysis and hence requires demonstration that the method is appropriate for the given substance or product and gives a result consistent with that obtained with the prescribed method as described in the General Notices"  The additions under paragraph 13. "Replacement of Methods prescribed in Monographs" are of particular importance. In section 2, you can find information about the replacement by methods not described in the PH.EUR:  "The use of alternative reagents such as recombinant factor C as a replacement to the amoebocyte lysate eliminates the use of live animals. Replacement of a rabbit pyrogen test or a bacterial endotoxin test prescribed in a monograph by a test using recombinant factor C or any other reagent as a replacement of the amoebocyte lysate is to be regarded as the use of an alternative method in the replacement of a pharmacopoeial test, as described in the General Notices: “The test and assays described are the official methods upon which the standards of the Pharmacopoeia are based. With the agreement of the competent authority, alternative methods of analysis may be used for control purposes, provided that the methods used enable an unequivocal decision to be made as to whether compliance with the standards of the monographs would be achieved if the official methods were used. In the event of doubt or dispute, the methods of analysis of the Pharmacopoeia are alone authoritative.” Australian TGA updates eCTD FAQ The Australian Therapeutics Good Administration has updated their "Australian eCTD submissions: Frequently asked questions" website. The update concerns more or less the whole list of questions and answers presented earlier. Many new questions have been introduced and some earlier ones have now been addressed in more detail.
  23. 23. PHARMA UPTODAY 23 Pilot phase My company wants to join the Pilot - can we send an eCTD submission directly to the TGA? During the pilot phase, we ask Sponsors to contact esubmissions@tga.gov.au if you wish to be involved for any specific application. Decisions on which applications will be included in the pilot phase are being made on a case by case basis. This allows us to find the best test cases so we can be prepared for the implementation of eCTD. Do not send your submission without first confirming your participation in the pilot for your specific application. An application from our company has been accepted onto the Pilot, can we submit other applications to the Pilot? During the pilot phase, we ask Sponsors to contact esubmissions@tga.gov.au if you wish to be involved for any specific application. Decisions on which applications will be included in the pilot phase are being made on a case by case basis. This allows us to find the best test cases so we can be prepared for the implementation of eCTD. Do not send your submission without first confirming your participation in the pilot for your specific application. What is the scope of the eCTD pilot phase? The pilot phase will test capabilities of submitting electronic Common Technical Documents (eCTD) for registered prescription medicines. The TGA will work with sponsors to identify suitable prescription medicine eCTD submissions to pilot and test aspects of the TGA electronic submission application process internally and externally. We are looking to test the following prescription medicines application types:  new chemical entity  major variations to a prescription medicine (both with and without baseline)  generic medicine. Decisions on which prescription medicine applications will be included in the pilot phase are being made on a case by case basis. This allows us to find the best test cases so we can be prepared for the implementation of eCTD. What formats should we submit in during the pilot phase? During the eCTD pilot phase, submissions from sponsors participating in the pilot will be in the eCTD format. If you are not participating in the pilot phase all requirements for an effective submission, including the need to submit a paper copy of the dossier, will stay the same. What will happen when the pilot finishes in February 2015? The TGA will conduct a readiness assessment to determine the success of the eCTD Pilot and readiness of Industry to participate further. Will I be required to submit applications in eCTD format after February 2015? No. The two (2) legal instruments will allow for submission of either eCTD format or as is currently accepted. The TGA encourages sponsors / applicants to move to eCTD submissions to reduce costs and regulatory burden.
  24. 24. PHARMA UPTODAY 24 General What type of therapeutic goods will the eCTD format be acceptable for? The eCTD format will be accepted but not made compulsory for prescription, biological and registered non-prescription medicines. Medical devices will not be included in the initial stages of the TGA moving to accept eCTD submissions. Medical devices are likely to be included when the international standard for Regulated Product Submissions is sufficiently stable. There is no requirement for new listable substances (active and excipient), new sunscreen active substances and new excipients in topical non-prescription medicines to follow the eCTD format. Will an eCTD submission to the TGA require accompanying paper copies? Submissions in the eCTD format will not need to be accompanied by a paper copy of the dossier. To support this activity the TGA has added a second Section 23 instrument, which enables lodgment of an eCTD submission without paper in the pilot program. Are there any submission types that will not need to be submitted in eCTD format (Good Manufacturing Practice certificates, Periodic Safety Update Reports, etc.)? The eCTD format is regarded as the principal electronic submission format for medicines in Australia. TGA expects that all submissions will be able to use the eCTD format including registration applications, master files and Periodic Safety Update Reports. If there is a product with more than 1 'container/vial' size and a separate ARTG entry for each of these sizes, will there need to be separate eCTD applications for each of the ARTG listings? e.g. 5ml, 10ml and a 20 ml vial of the same product? The normal choice should be one single eCTD application that covers multiple drug products (components), multiple dosage forms, multiple strengths and multiple manufacturers. If the applicant needs to have one eCTD application per strength, dosage form, etc., this should be explained. The cover letter should describe how the documentation may be similar or different in order to prevent the duplication of work during evaluation. Will we have access to the eCTD once submitted to TGA i.e. online so that we can see our application live? There are no plans to allow online access to TGA stored submissions. Who will have access to the eCTD information once the dossier is submitted to TGA and once the product is approved? Only authorised TGA staff will have access to submissions information. This is no different to current TGA work practices and guidelines. Does the TGA recommend or welcome applicants submitting 'test eCTD submissions' to the TGA? The TGA expects sponsors and applicants to use validation tools to test their own eCTD applications before submitting them to the TGA. A copy of the validation report will need to be
  25. 25. PHARMA UPTODAY 25 attached to the submission. Validation tools are available from software vendors or an example tool can be downloaded from the TGA website. Will a submission be given review priority by virtue of it being in the eCTD format and are there going to be any incentives for submitting in eCTD? Over time, processes may become more efficient as we use eCTD, but at this stage there are no plans to give applications submitted in the eCTD format review priority or provide any additional incentives to submit in eCTD format. eCTD will assist the TGA and sponsors by reducing regulatory burden and removing the requirement to produce unnecessary and burdensome paperwork. How can industry contribute to the development of new guidance material? Interested parties are welcome to forward comments on TGA's eCTD guidance documents at any time. It is expected that guidance documents will be further modified at intervals based on comments received, experience gained, and further ICH developments. Comments may be forwarded to the TGA and we will review all requests and comments for inclusion in consultation with stakeholders. Information for IT specialists and information managers Which software products are best suited to compile eCTD submissions? Sponsors and applicants are free to use any appropriate software to compile and publish eCTD submissions. The TGA also requires a validation report to be attached to each submission. Submissions must pass the TGA's validation processes to be accepted. Does TGA recommend the use of eCTD viewing tools and if so should this be the Lorenz tool? TGA does not recommend any specific eCTD tools. However, there are a number of software vendors in the marketplace. What is the maximum file size of an entire eCTD submission that is accepted by the TGA? The maximum size of an individual PDF file is 100MB. There is no maximum for the entire submission. The TGA will encourage submission via DVD during the Pilot and until we have a fully developed portal facility with capacity for upload. Can industry download a template folder structure for eCTD/NeeS from the TGA website, as the Belgium Federal Agency for Medicines and Health Products has on their website? Currently there are no plans for this function. Is the TGA considering moving to RPS (eCTD 4.0) in the future? The TGA is planning for RPS (eCTD 4.0). Information for regulatory affairs areas Will the eCTD dossiers be submitted via the TGA eBS portal? No, not initially. eCTD submissions will be submitted via electronic media. A future project phase will examine portal requirements.
  26. 26. PHARMA UPTODAY 26 It is envisaged that registered non-prescription medicine submissions can continue to use the eBS portal as is used currently. This will be confirmed in initial testing. Will all variations be submitted via eCTD or just new registration applications? TGA is piloting a range of types of submissions. Subject to the outcomes of these pilots, we expect to be able to receive all types of submissions, including variations (with and without baseline eCTD submissions), in the eCTD format. Once a submission for a product is submitted in the eCTD format, all future submissions related to that product must be in the eCTD format. How can we prepare for eCTD? Experience from Sponsors who are using eCTD to submit to overseas regulators has shown there are four areas to manage in order to be prepared: 1. Standards: including data standardization and harmonization, using style guides and templates (for example, authoring templates and standardising headers and footers), understand and following the guidance from the regulator and applying component authoring standards 2. Process: having processes to support authoring and importing, review, approving, publishing and submission, lifecycle management and system validation 3. Technology: acquiring or using document management, publishing and data management software. Knowledge of XML authoring and publishing and having the correct IT infrastructure and network capacity in place. 4. Organisation: supporting people through global collaboration and training. Planning for your submission needs to include the estimated time for publishing and aligning your processes to the requirements of the TGA. Should we use tradenames in eCTD? No, use the drug or chemical name. Transition When will we know about the transition phase? An evaluation of the pilot project will occur in February 2015. Information on the transition to eCTD will be announced when the evaluation has been completed. Can I swap between eCTD submissions and NeeS? Once a submission for a product is submitted in the eCTD format, all future submissions for that product must be in the eCTD format. Will the TGA need to be informed in advance of the intention to transition an application to eCTD? No, but once commenced in the eCTD format applicants should remain in the eCTD format in order to take advantage of the lifecycle features of the eCTD standard (i.e. applicants do not have to re-submit documents already submitted to the TGA). Submission and sequence numbers Can we set our own eSubmission identifier numbers or does the TGA intend to issue numbers that we need to track the application with?
  27. 27. PHARMA UPTODAY 27 Submissions will require a TGA eSubmission Identifier, issued by TGA, in the 'envelope' information for each submission. Submissions will be referenced by this number and therefore subsequent sequences must include this identifier. How do I get an eSubmission Identifier from the TGA? To get an eSubmission Identifier, send an email to esubmissions@tga.gov.au with the applicant's name, the Australian Approved Name, and description of the application (trade names, dose form, strength and route of administration). When submitting via eCTD will correspondence to the TGA need to be in eCTD format or can industry still send documents via email? Documents and significant correspondence should be via eCTD sequences (e.g. responses to requests for additional information). If NeeS dossiers have already been submitted, does this affect the eCTD sequence number? No. The first eCTD submission for any product (including a new dossier or the accumulated documents to date of an existing product) normally has a sequence number of 0000, even if sequential numbers were already used for a NeeS submissions of the same product. If applicants consider that there are good reasons to use another number they should seek agreement from the TGA and provide the explanation in the cover letter. If a baseline eCTD submission is provided, the baseline should normally be submitted as sequence 0000. The baseline is a separate submission and should not include any requests for new regulatory actions. The first new regulatory activity relating to a product, e.g. the next variation, in eCTD format should then be submitted as sequence 0001. Can we set our own sequence numbers to track our applications or does the TGA intend to generate these? Sequence numbers for a particular submission start at 0000 and increment by 1 each time. The TGA is considering the approach where baselines and New Chemical Entity (NCE) submissions start with sequence 0000. In all other cases, submissions should commence with sequence 0001. This would act as a marker that previous documents are outside the eCTD system. If an Applicant transfers part ownership (say one of the Trade Names) then the New Applicant would receive a new eSubmission Identifier and the next sequence number would be the next sequence as per the original eSubmission Identifier. This enables the New Applicant to refer to the existing documents and not have to re-submit. Part of the transfer arrangement would be agreement to access the existing dossier. Do eCTD sequence numbers need to run sequentially or can eCTD submission be sent out of sequential order (e.g. a delay submitting sequence 0012 means sequence 0013 is submitted before 0012)?
  28. 28. PHARMA UPTODAY 28 Sequence numbers will normally run sequentially. The TGA validation process will give a warning that an out of sequence submission has been detected. If a sequence number is out of order, then the applicant should state in the cover letter why the sequence is out of order in order to minimise any delays in the process. Validation requirements Will the TGA release a list of the validation criteria for eCTD? The TGA validation criteria will be available on the website. Will the TGA notify the sponsor if there are any validation errors after submitting the eCTD to the TGA? Will there be time for validation errors to be fixed before the eCTD is technically rejected? The TGA expects sponsors and applicants to use validation tools to test their own eCTD applications before submitting them to the TGA. A copy of the validation report will need to be attached to the submission. Validation tools are available from software vendors or an example tool can be downloaded from the TGA website. TGA will adopt a set of technical validation criteria against which all eCTD and NeeS sequences can be checked. Two categories of validation rules apply: 'Pass/Fail', and 'Best Practice'. The technical validation of an eCTD or NeeS formatted submission is a separate activity to the content validation of a submission and takes place irrespective of the type of the submission. Sequences which fail to meet one or more of the 'Pass/Fail' criteria will be returned to the applicant for correction and resubmission. TGA may accept sequences which fail to meet one or more of the 'Best Practice' criteria; however, the applicant should make every effort to address these areas before the eCTD is submitted to TGA. Document requirements What is the working documents folder for and what should be submitted in this folder? Non-PDF file formats such as rich text (RTF) or MS Word formats may be required by agencies in addition to the PDF requirements of the eCTD and NeeS, for example, the provision of Product Information documents. The files referred to above should not be added as leaf elements within the eCTD/NeeS structure. When submitted with an eCTD/NeeS formatted submission, they should always New USP Chapters on Storage and Distribution under Way - but what is the Relevance? The Pharmacopoeial Forum 40(2) presents the five new General Chapters on Storage and Distribution. In June 2014, the USP announced under "Compendial Updates" that the deadline for comments on these General Chapters would be extended to the end of August 2014. It concretely addresses the following 5 General Chapters:  <1083> Good Distribution Practices  <1083.1> Quality Management System
  29. 29. PHARMA UPTODAY 29  <1083.2> Environmental Conditions Management  <1083.3> Good Importation and Exportation Practices  <1083.4> Supply Chain Integrity and Security These new chapters are supposed to replace the current ones <1079> and <1197> on storage and transportation of medicinal products and pharmaceutical excipients. An essential prerequisite for the right storage and correct transport lies in the selection of an appropriate packaging system which ensures the necessary protection for the medicinal product; like, for example, desiccants or packaging materials which protect against light. The pharmaceutical packaging has to comply with the protection requirements of the material or product. Also the environmental influences (temperature, rel. humidity, etc.) have to be considered to enable transportation and storage of the medicinal product without any essential loss of quality. You can find the complete text about the deadline extension as well as the five chapters on the USP website. Now it will be interesting to see which proposals will be incorporated into these new chapters to be published in one of the next editions of USP/NF. The stakeholders involved in the global supply chain need clear guidance on what measures need to be implemented to ensure a secure transport and storage of medicinal products. But what is the relevance of the USP chapters when they are finalised? FDA normally refers to the USP and even enforces USP standards. However, USP standards above the number 1000 (as it is the case with the GDP chapters described above) will not be enforced but are considered to be state of the art. In Europe the EU Commission has publised a GDP Guideline which is more concrete and is the official basis for GDP Inspections. The GDP Guide is already available in 22 different languages. The USP chapter might therefore cause confusion about what is expected for those companies dealing with products for the EU and US market. Harmonisation in the field of GDP is needed to make sure that standards are the same and that enforcement can be performed by using one uniform standard.
  30. 30. PHARMA UPTODAY 30 AUDIT FINDINGS - 483 Observations Firm Name 483 Observation Amneal Pharmaceuticals Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity Novartis Vaccines and Diagnostics GmbH A disinfectant effectiveness study was not completed. TG United Liquid, Inc. An adequate number of batches of each drug product are not tested nor are records of such data maintained to determine an appropriate expiration date. Guest Packaging, LLC Laboratory records do not include complete records of any testing and standardization of laboratory reference standards. Elite Laboratories, Inc. The responsibilities and procedures applicable to the quality control unit are not fully followed. A & Z Pharmaceutical, Inc. Reserve samples from representative sample lots or batches of drug products selected by acceptable statistical procedures are not examined visually at least once a year for evidence of deterioration. American Family Pharmacy, LLC Batch production and control records do not include complete information relating to the production and control of each batch. Dhaliwal Laboratories, LLC Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use. Wells Pharmacy Network, LLC Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written, and followed. Amylin Ohio, LLC Written production and process control procedures are not followed in the execution of production and process control functions. The Methodist Hospital Research Institute PET Facility You did not establish procedures to investigate the cause(s) of the nonconforming batch(s) of a PET drug product. Qualitest Pharmaceuticals The plumbing system contains defects that could contribute to the contamination of drug products. A & Z Pharmaceutical, Inc. Buildings used in the manufacture, processing , packing, or holding of a drug product do not have suitable construction and location to facilitate cleaning, maintenance, and proper operations.
  31. 31. PHARMA UPTODAY 31 Apotex Research Private Ltd. There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has already been distributed. Midwest Medical Isotopes, LLC You did not establish written quality assurance procedures. 483 of Exemplar Lab, MA Observations: 1. The in process control procedures were deficient in that they did not include an examination of the adequacy of mixing to assure uniformity and homogeneity 2. 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. Genentech Inc Receives 483 from US FDA 1. Written records of investigations into unexplained discrepancies and the failure of a batch or any of its components to meet specifications do not include the conclusions and follow-up. 2. Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use. 3. There was a failure to handle and store closures at all times in a manner to prevent contamination. 4. Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not followed. Celltex Therapeutics Corporation 483 Observations: 1. Control procedures are not established which validate tho performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. 2. Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written, and followed. 3. Written records are not made of investigations into the failure of a batch or any of its components to meet specifications.
  32. 32. PHARMA UPTODAY 32 4. Drug product production and control records, are not reviewed by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. 5. Batch production and control records do not include complete information relating to the production and control of each batch. 6. Equipment used in the manufacture, processing, packing or holding of drug products is not suitably located to facilitate operations for its intended use. 7. HCT/Ps made available for distribution were not labeled accurately. 8. The distinctive code for each lot of components is not used in recording the disposition of each lot. 9. Each lot of components was not appropriately identified as to its status in terms of being quarantined, approved or rejected. 10. Routine calibration and checking of equipment is not performed according to a written program designed to assure proper performance. 11. The batch records do not record the distinctive identification number and code to Identify major equipment to show the specific equipment used in the manufacture of a batch of a drug product. 12. Written procedures are lacking which describe in sufficient detail the identification and handling of components. 13. Distribution records do not contain the name and strength of the drug product, description of dosage form, name and address of consignee, date and quantity shipped, and lot or control number of drug product. 14. Washing and.toilet facilities are not easily accessible to working areas. APP Pharmaceuticals, LLC (Sterile Drug Manufacturer), NY - 483: Observations: Quality Systems: 1. There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed. 2. Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process. 3. Records of returned drug products are not maintained. Facilities and Equipment: 4. Buildings used in the manufacture, processing, packing or holding of drug products are not free of infestation by rodents, birds insects, and other vermin.
  33. 33. PHARMA UPTODAY 33 5. Equipment used in the manufacture, processing, packing or holding of drug products is not suitably located to facilitate operations for its intended use. Production System: 6. Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not written and followed. 7. Deviations from written production and process control procedures are not justified. 8. Master production and control records lack complete manufacturing and control instructions, special notations, and precautions to be followed. 9. Procedures for the preparation of master production and control records are not followed. Laboratory Systems: 10. Laboratory controls do not include the establishment of scientifically sound and appropriate sampling plans and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity. 11. Acceptance criteria for the sampling and testing conducted by the quality control unit is not adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release. 12. Reserve samples from representative Jots or batches of drug products selected by acceptable statistical procedures are not examined visually at least once for evidence of deterioration. 13. Verification of the suitability of the testing methods is deficient in that they are not performed under actual conditions of use. 14. Input to and output from the computer and related systems of formulas are not checked for accuracy. Material Systems: 15. Drug product container and closure test procedures are deficient in that containers are not tested for conformance in accordance with appropriate written procedures. Other Post Marketing Reports: 16. 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. FDA 483 of Reganeron Pharmaceuticals, Inc. 1. Following a number of failing "clean bold validation studies" for multiple equipment based on bioburden endotoxin results which did not meet acceptance criteria and which were concluded to be related to the WFI supply to those specific equipment
  34. 34. PHARMA UPTODAY 34 2. There are no security measures employed in the issuance of'worksheets in the raw material testing laboratory located in building II Inspection found that it is possible to print additional uncontrolled blank worksheets. 3. Review of the firm's manual log for SCARs (Supplier Corrective Action Requests) which was stated to be the'original, GMP document for tracking these events found numerous entries for the past two years which were not closed out. This log is used for tracking of potential quality issues related to raw materials received from vendors. 4. The firm's written procedure SOP GE515 'Investigation and handling of out-of..specification (OOS) and Atypical Test Results" fails to provide adequate instructions regarding the follow-up to stability test failures for marketed product. 5. The role of the ''reimbursement vendor' in providing information related to quality complaints and the documentation in the 'complaint file of communications with that agent is not adequately addressed in the applicable complaint handling procedure. 6. Quality Assurance review of data included the report of investigation follow-up to complaints 08-009, 08-010 and 08-011 of lack of efficacy for Arcalyst, lot B070012A was inadequate in that it failed to detect that the peptide mapping profiles of fully glycosylated and deglycosylated rilanocept show no significant differences in the retention time. FDA Warning letters Hospira, Austarlia plant gets Warning letter from US FDA GMP Violations are as follows: 1. Your firm failed to thoroughly investigate unexplained discrepancies or failures of a batch or its components to meet its specifications, whether or not the batch has already been distributed (21 CFR 211.192). a. Several out-of-specification (OOS) results for the impurity (b)(4) ((b)(4)) from the stability studies of multiples batches of (b)(4) Injection were inadequately investigated. b. No effective corrective action and preventive action plan were implemented to address the recurrent findings of foreign matter (specifically, (b)(4) particles) in (b)(4) injection drug product. 2. Your firm failed to establish written procedures for production and process control designed to assure 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 aseptic processing areas (21 CFR 211.42(c)(10)(iv)).
  35. 35. PHARMA UPTODAY 35 China Resources Sanjiu Medical and Pharmaceutical Co., Ltd. 9/19/14 (WL: 320-14-17) CGMP VIOLATIONS 1. Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specification for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165 (a)). Specifically, your firm manufactures Ganmaoling Cold Granule and Ganmaoling Cold Capsule drug products containing three active pharmaceutical ingredients (APIs): acetaminophen, chlorpheniramine maleate, and caffeine. However, you only verify by assay one of the three APIs, acetaminophen, at the time of batch release. In your response, you indicate that your Ganmaoling Cold Granule and Ganmaoling Cold Capsule drug products are manufactured according to the Chinese National Legal Standard, which only requires an assay test for acetaminophen. If your product is intended for the US market it is required to meet US quality standards and each active ingredient must be tested to verify its labeled strength. 2. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160 (b)). For example, your firm has not established a release specification and test procedure to determine the level of impurities in the Ganmaoling Cold Granules and Ganmaoling Cold Capsule drug products. You have not determined an impurity profile for these products. In your response, you state that you are not able to separate the APIs and impurities effectively by HPLC or TLC due to the drug products’ complicated formulation and that you need to continue your research to identify a suitable method. Please be advised that if you intend to legally market in the US and apply for a new drug application, you will be required to submit scientifically sound and appropriate specifications and testing methods for purity, impurity, release, and stability. 3. Your firm failed to establish an adequate written testing program designed to assess the stability characteristics of drug products, and to use the results of such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166 (a)).
  36. 36. PHARMA UPTODAY 36 Specifically, your firm does not perform stability testing on chlorpheniramine maleate and caffeine for assay. You lack stability data to support the (b)(4) expiry period assigned to your Ganmaoling Cold Capsules and Ganmaoling Cold Granule drug products. Please be advised that if you intend to legally market in the US and apply for a new drug application, you will be required to submit an adequate written stability testing program and results to support your determination of appropriate drug product storage conditions and expiration dates. 4. Your firm failed to use equipment constructed in a way that surfaces that contact components, in- process materials, or drug products are not reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirement (21 CFR 211.65(a)). For example, after (b)(4), the product is (b)(4) through (b)(4). The inspection documented that the (b)(4) material frequently breaks, resulting in (b)(4) particles in the (b)(4). Although you change the (b)(4) every (b)(4) in an attempt to prevent its breakdown, this appears to be an inadequately designed process using an inappropriate piece of equipment. We also note that your firm uses a (b)(4) after (b)(4) to remove any (b)(4) particles that may be introduced into the (b)(4) during the process. However, your firm did not qualify this equipment prior to use, and you are not able to provide documentation to support the consistent performance and operation of this equipment. Source: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm417424.htm Beacon Hill Medical Pharmacy, P.C. 9/24/14 (2014-DET-17) 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 and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)). 2. Your firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(v)). 3. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination (21 CFR 211.28(a)).
  37. 37. PHARMA UPTODAY 37 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 establish an adequate air supply filtered through high-efficiency particulate air filters under positive pressure in the aseptic processing areas (21 CFR 211.42(c)(10)(iii)). 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)) 7. 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)). Source: http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm418709.htm
  38. 38. PHARMA UPTODAY 38 AUDIT FINDINGS - EMA Non Compliance Reports Non-Compliance Report of Wockhardt Limited, Nani Daman, India Nature of non-compliance : 1 Critical deficiency : Issues were identified which compromised the integrity of analytical data produced by the QC department. Evidence was seen of data falsification. A significant number of product stability data results reported in the Product Quality Reviews had been fabricated. Neither hard copy nor electronic records were available. In addition issues were seen with HPLC electronic data indicating unauthorised manipulation of data and incidents of unreported trial runs prior to reported analytical runs. 3 Major deficiencies 1. The product stability monitoring programme had not been maintained to cover products currently on the market. 2. Quality Control deficiencies including; inadequate records, lack of specificity in analytical methods, failure to investigate unknown peaks and non-compliance with MA details. 3. Deficiencies in material cold storage arrangements. The site was re-inspected on [28 April to 1 May 2014]. The company’s remediation plan remains in progress, and compliance has not yet reached a satisfactory level. No change in product risk was identified as a result of the re-inspection, and no changes to existing regulatory action are proposed. The company remains under close regulatory supervision. Non-Compliance Report: Fujian South Pharmaceutical, China Nature of non-compliance : In total 27 deficiencies were found by the inspection team, whose opinion is that two of them constitute a risk to the patient and were hence categorised as critical and related to the Quality Control System and to the implementation of sound computerised systems, including data integrity issues. Furthermore three major deficiencies were observed in the field of building and facilities, documentation and laboratory controls. Here below a brief summary of the Critical and Major deviations:
  39. 39. PHARMA UPTODAY 39 [Critical] The inspection team tried to verify some regulatory information requested during the assessment of the dossier and reached the conclusion that fundamental GMP and regulatory requirements such as loss of data integrity, combined with insufficient management of data, change control system, supplier qualification, laboratory controls as well as the accuracy of data submitted, were not adequately implemented/considered because of a weakness of the QA system and regulatory affairs department; [Critical] Severe GMP violations related to the implementation of sound computerised systems in the quality control facilities were committed, that could lead/could have led to the falsification of data. It was impossible to verify that the decision to approve raw material and final API was based on valid and accurate data; [Major] In workshop B-03 the room used to perform the first purification of Docetaxel anhydrous by liquid chromatography was found not suitable for its intended use, as there was a potential risk of contamination; [Major] The issuance of quality related documentation was found inadequately controlled/secured by QA; [Major] The Company’s manufacturing process C for Docetaxel anhydrous requires the blending of individual batches. The insufficient equipment capacity requires the material previously obtained to be split into two single batches. The manufacturing operations to be conducted in the final purification step are four crystallisations followed by drying. No testing of the individual batches was required prior to the blending operation. This approach could lead to masking of Out-of-Specification results in the individual batches. The remaining 22 deficiencies identified some additional issues in the field of Quality Management, Buildings and Facilities, Process Equipment, Documentation and Records, Laboratory Controls, Validation, Rejection and Re-use of Materials.
  40. 40. PHARMA UPTODAY 40 Regulations of the Month Subpart J--Records and Reports § 211.184 Component, drug product container, closure, and labeling records. These records shall include the following: (e) The disposition of rejected components, drug product containers, closure, and labeling. § 211.186 Master production and control records. (a) To assure uniformity from batch to batch, master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person. The preparation of master production and control records shall be described in a written procedure and such written procedure shall be followed. § 211.186 Master production and control records. (b) Master production and control records shall include: (1) The name and strength of the product and a description of the dosage form; (2) The name and weight or measure of each active ingredient per dosage unit or per unit of weight or measure of the drug product, and a statement of the total weight or measure of any dosage unit; (3) A complete list of components designated by names or codes sufficiently specific to indicate any special quality characteristic; (4) An accurate statement of the weight or measure of each component, using the same weight system (metric, avoirdupois, or apothecary) for each component. Reasonable variations may be permitted, however, in the amount of components necessary for the preparation in the dosage form, provided they are justified in the master production and control records
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