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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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What GMP Changes can we still expect for 2014?
What GMP Changes can we still expect for 2014?
Heraclitus once said: “There is nothing permanent except change”. This statement is even true for the rather conservative GMP environment. What can we still expect for 2014? The answer to that question can be found in a work plan of EMA’s GMP/GDP Inspectors Working Group.
What are the coming plans?
- Finalising the changes planned for the Chapters 3 and 5 of the EU GMP Guide
- Finalising the revision of Chapter 8 of the EU GMP guide (with regard to product shortage notifications and specific risk management concepts)
- Agreeing, in consultation with PIC/S, whether guidance is needed on biofilms concerning Annex 1 of the EU GMP Guide
- Finalising the revision of Annex 15 of the EU GMP Guide (comparison with the new EMA process validation guideline and inclusion of necessary changes in the light of ICH Q 8-10)
- Finalising the revision of Annex 16 of the EU GMP Guide
- Finalising the revision of Annex 17 of the EU GMP Guide
- Further measures regarding the EudraGMDP database
The finalisation of the revision of Chapter 6 (Quality Control) of the EU GMP Guide is already completed (April 2014). The revised chapter will apply as of October 2014.
The following topics are also addressed in the work paper:
- Inspections under the centralised system
- Mutual Recognition Agreements (MRAs)
- Harmonisation topics
- Collaboration with the EU Commission (the collaboration should enable by the end of 2014 the publication of the GDP guidelines for APIs and the risk assessment guidelines to establish GMP for excipients)
- Collaboration with other groups (i.e. Reverse Osmosis for the production of WFI and biological indicators for monitoring and the control of sterilisation are topics addressed together with the EDQM in Strasburg)
Please also see the complete “Work plan for GMP/GDP Inspectors Working Group for 2014“.
Stability Data for ANDAs in the USA: a new Q&A Document of the FDA provides further Clarity
Stability Data for ANDAs in the USA: a new Q&A Document of the FDA provides further Clarity
The applicant for an ANDA in the USA has to submit data of several stability tests. The FDA guidance on this topic coming into force last year left open some issues, however, that now are clarified with a questions and answers document published lately.
Read more.
Stability Data for ANDAs in the USA: a new Q&A Document of the FDA provides further Clarity
The FDA Guidance for Industry with the title “ANDAs: Stability Testing of Drug Substances and Drug Products” was published in the Federal Register on 20 June 2013 (also see our News dated 1 August 2013) and is addressed to applicants for ANDAs in the USA. This guidance describes the stability data the FDA expects in the documents submitted for an ANDA and is rather short having only five pages. As expected, the FDA received vast amounts of questions concerning certain problems that were not answered clearly in the guidance. Therefore, the Agency was prompted to address these questions in a questions and answers document. This document has the title “ANDAs: Stability Testing of Drug Substances and Drug Products – Question and Answers” and was published on the FDA “Guidance”-Website in May 2014.
The questions and answers are addressed in the following five chapters:
- A. General
- B. Drug Master File
- C. Drug Product Manufacturing and Packaging
- D. Amendments to Pending ANDA Application
- E. Stability Studies
Some of the case studies discussed in these chapters are rather complex and therefore are answered in detail. In the following some questions and answers are listed for each chapter by way of example.
A. General
Question: Can an ANDA be submitted with 6 months of accelerated stability and 6 months of long-term stability data?
Answer: Yes. An ANDA applicant should submit this data. However, if 6 months of accelerated data show a significant change or failure of any quality attribute, the applicant should also submit 6 months of intermediate data at the time of submission.
Question: In the event of an adverse change of quality attributes at accelerated condition: When do intermediate stability studies need to be initiated?
Answer: An ANDA applicant should start accelerated, intermediate, and long-term stability studies at the same time so the data are available at the time of submission, if needed.
Question: During the review cycle, will the application need to be updated with 12 months of long-term data?
Answer: Yes. FDA will grant a shelf life period to the drug product of two times the available long-term data at the time of approval (up to 24 months). This is on condition, however, that the submitted stability data are satisfactory, and data evaluation and appropriate commitments are provided. With this the authority follows a recommendation of the Guideline ICH Q1E.
B. Drug Master File
Question: How many months of long-term and accelerated data are required when a “Completeness Assessment” is performed on the Drug Master File? Also, what should the stability section contain for a Completeness Assessment?
Answer: To pass the Completeness Assessment, the DMF should include the stability protocol and commitments. It also should contain data demonstrating that stability studies have started. The initial and one additional time point for the accelerated studies and long-term studies are sufficient. If the DMF does not meet the requirements for a successful assessment (see the following question/answer) the DMF holder must hand in updated stability data later.
Question: Are stability data from three current good manufacturing practice (CGMP) batches required to be filed in the DMF to support the active pharmaceutical ingredient retest date? How many months of long-term and accelerated data are required for pilot scale batches?
Answer: Yes. The DMF should contain data from stability studies on at least three primary batches of the API (these batches should be made under cGMP conditions) and the batches should be manufactured to a minimum of pilot scale (also see ICH Q1A(R2)).
The FDA stability guidance recommends 6 months of accelerated data and 6 months of long-term data for the pilot scale batches to be submitted for a full scientific review of the DMF. Additional long-term data for all three batches, as the data becomes available through the proposed retest period, should be submitted as an amendment.
C. Drug Product Manufacturing and Packaging
Question: What is the Agency’s position on using different lots of APIs and/or packaging materials? How many API lots should be used in the manufacture of finished product lots used to support the ANDA?
Answer: It is not necessary to use different lots of packaging material, except in cases where the packaging material could affect drug product performance and/or delivery.
A minimum of two lots of the drug substance should be used to prepare the three primary batches of drug product. For nasal aerosols and nasal sprays, you should use three different lots of drug substance.
Question: Should the small scale batches be packaged with commercial equipment? Is it acceptable to package using research equipment?
Answer: Yes. Small scale batches should be packaged with commercial equipment. Anyway, the packaging equipment should be similar to that proposed for use prior to market distribution.
No, it is not recommended to package small scale batches using research equipment or by hand. …
D. Amendments to Pending ANDA Application
Question: What are the recommendations for amendments and responses filed to pending ANDAs after issuance of the final FDA stability guidance?
Answer: All amendments submitted to pending ANDAs after the effective date of the final FDA stability guidance will be held to the standards in place concerning stability data at the time of the original ANDA submission, unless there is a concern with the submitted stability data.
E. Stability Studies
Question: Can the Agency clarify expectations for the storage positions for products placed into the stability program?
Answer: For primary batches of liquids, solutions, semi-solids, and suspensions, the product should be placed into an inverted (or horizontal) position and an upright position. For routine stability studies, the applicant should pick the worst case orientation for the study.
Question: Can the Agency clarify expectations around the number of batches to support tests such as preservative effectiveness and extractable leachable testing?
Answer: One of the primary batches of the drug product should be tested for antimicrobial preservative effectiveness (in addition to preservative content) at the end of the proposed shelf life. The drug product specification should include a test for preservative content, and this attribute should be tested in all stability studies.
Extraction/leachable studies are generally one-time studies. However, if multiple types of containers/closures are employed for packaging, then additional studies could be recommended.
The FDA tries to clarify the cases described in this Q&A document as clear and as much in detail as possible. In doing so the Agency complements its declarations by numerous indications concerning the provisions in the ICH guidelines Q1A(R2), Q1D, Q1E and in 21 CFR Part 211. Thereby, this very important and updated document covers most situations with regard to stability testing for ANDAs.
The US FDA has issued a Warning Letter to Tianjin Zhongan Pharmaceutical Co. Ltd. in Tianjin, China.
FDA issues Warning Letter for API Facility
http://www.gmp-compliance.org/enews_4367_FDA%20issues%20Warning%20Letter%20for%20API%20Facility_8509,S-WKS_n.html
The US FDA has issued a Warning Letter to Tianjin Zhongan Pharmaceutical Co. Ltd. in Tianjin, China. The company produces APIs and failed to establish adequate GMP procedures at the facility. Read more about the FDA Warning Letter.
FDA issues Warning Letter for API Facility
The US FDA has issued a Warning Letter to Tianjin Zhongan Pharmaceutical Co. Ltd. in Tianjin, China. The company produces APIs and failed to establish adequate GMP procedures at the facility.
For quite some time India was in the center of attention and very little was heard about GMP problems in China (see also RAPS article). This is a bit surprising because a number of non-compliant facilities have been detected in the past. Also the facilities which caused the Heparin Scandal were located in China. The last enforcement action from FDA which became public referred to Import Alerts for the manufacturer Zhejiang Jiuzhou Pharmaceutical and for Zhejiang Zonebanne in China.
The new Warning Letter for Tianjin Zhongan Pharmaceutical lists a number of different non compliance findings. These findings refer to equipment cleaning (risk of cross contamination), not adequate Change Control procedures and failure to adequately review and investigate product deviations. However, in difference to the Warning Letters sent to Indian manufacturers recently data integrity issues have not been detected.
Interestingly the API manufacturer Tianjin Zhongan Pharmaceutical is not listed in EudraGMDP the inspection database in the EU. No entry for GMP Certificates or GMP Non-Compliance Report are available.
Source: FDA Warning Letter to Tianjin Zhongan Pharmaceutical
Tianjin Zhong’an Pharmaceutical Company Ltd. locates in the southwest of Tianjin. Set up in 1988, the company underwent operation mechanism reform in 2002 and acquired the present name.
The company covers an area of 82,000 square meters, with a construction area of 31,600 square meters and an afforested area of 13,300 square meters. It has over 600 staff members, more than 50 of whom have been conferred intermediate or advanced titles of technical post. The company produces 10 major chemical bulk pharmaceuticals, including Caffeine, Theophylline, Aminophylline, Metronidazole, Metronidazole Benzoate, Nifedipine, Secnidazole and Xanthinol Nicotinate. Its annual production capacity amounts to 4000 ton, with a sales volume of approximately RMB 250 million. Two leading products in the company are Caffeine and Metronidazole.
Zhong’an Pharmaceutical enjoys a self-management power over import and export., 90% of its products are aimed at international market, with 60% of which sold directly to world-renowned pharmaceutical and beverage enterprises. It has established a sales network which covers more than 30 countries and regions, including some European and American countries, Hong Kong, Taiwan and Macao, countries in Southeast and Midwest Asia, and Russia.
Zhong’an Pharmaceutical has set up a full set of quality assurance system, and owns a central laboratory with advanced analyse instruments that has got the title of Export Enterprise Lab and approved by Tianjin entry-exit inspection and quarantine bureau. All workshops of the company are dedicated to avoid the issue of cross pollution. Every stage of production strict complies with the cGMP, which led to the products has been enjoying a high reputation both domestic and overseas market.
Since 2000, the company has obtained GMP and ISO9001certificates, and conferred the title of Tianjin High-new Tech Enterprise and Municipal-level Key Technical Center. Both of leading products Metronidazole and Caffeine have got COS issued by EDQM and DMF register number from US FDA. Also Caffeine has got “Foreign Manufacturer Validation Certificate” from Japan Health Ministry and KOF-K and Halal certificates.
US Orphan Drug Market Outlook 2018 ……….download available
US Orphan Drug Market Outlook 2018
Academia.edu
US Orphan Drug Pipeline Insight by Phase & Indication 5.1 Research 5.2 Preclinical 5.3 Phase I 5.4 Phase I/II 5.5 Phase II 5.6 Phase II/III 5.7 Phase III …
http://www.academia.edu/7453102/US_Orphan_Drug_Market_Outlook_2018 …………… download at this site
Market Overview
In the largest market for orphan drugs, USA, there was a shortage of adequate therapies for treating many rare diseases. These therapies were not developed as companies did not expect these drugs to be highly profitable. Hence there was a lack of interest and thus investment on the part of pharma companies in the USA. Therefore, the FDA introduced incentives for developing such drugs. This step taken by the FDA was successful in creating a thriving market for orphan drugs. It was in the USA first that a special law exclusively for governing orphan drugs was framed in the form of the Orphan Drug Act of 1983. This led to an increase in the popularity of orphan drugs. The FDA also has been continuously increasing its efforts to support this market by providing significant financial and non-financial incentives to the pharmaceutical companies to attract them. This has been one of the major drivers of growth for the US orphan drugs market.
Figure 3-1: US Orphan Drug Market (US$ Billion), 2012-2018
2012201320142015201620172018
Source: KuicK Research
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Study Finds Shu Gan Liang Xue Herbal Formula Has Breast Cancer Anti Tumor Effect
There are a host of herbal formulas that show anti tumor properties for various cancers in clinical studies. Chinese researchers publishing in the Journal of Ethnopharmacology recently conducted a study looking at the effect of Shu Gan Liang Xue Formula on breast cancer tumors – particularly estrogen receptor positive breast cancer line ZR-75-1. Researchers investigated these anti-tumor functions in vitro and in vivo.
Shu Gan Liang Xue is a traditional Chinese herbal formula, it is comprised of the following herbs:
- Chai Hu
- Bai Shao
- Wu Wei Zi
- Dan Pi
- Bai Wei
- Zi Cao
Researchers understand that estrogen is a driver behind breast cancer. Two other substances, aromatase and steroid sulfatase are enzymes which contribute to estrogen synthesis. The researchers found that Shu Gan Liang Xue inhibits aromatase and steriod sulfatase which decreases their expression and their effect of estrogen synthesis. They found this both in vitro and in vivo.
In addition to…
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Too-clean homes may encourage child allergies, asthma
http://www.live5news.com/story/25711359/too-clean-homes-may-encourage-child-allergies-asthma-study
(HealthDay News) — Cleanliness may be next to godliness, but a home that’s too clean can leave a newborn child vulnerable to allergies and asthma later in life, a new study reports.
Infants are much less likely to suffer from allergies or wheezing if they are exposed to household bacteria and allergens from rodents, roaches and cats during their first year of life, the study found.
The results stunned researchers, who had been following up on earlier studies that found an increased risk of asthma among inner-city dwellers exposed to high levels of roach, mouse and pet droppings and allergens.
“What we found was somewhat surprising and somewhat contradictory to our original predictions,” said study co-author Dr. Robert Wood, chief of the Division of Allergy and Immunology at the Johns Hopkins Children’s Center in Baltimore. “It turned out to be completely opposite — the more of those three allergens…
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Odor Code for Food Based on a Few Volatile Substances
The actual flavor of a food is experienced through our sense of smell rather than with our tongue. However, of the large number of volatile compounds in foods, only about 230 are involved in the scent, as reported by German scientists in the journal Angewandte Chemie. The different smells derive from characteristic combinations of three to forty of these odorants.
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 