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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Is there something like Authorities’ approved production equipment?
Is there something like Authorities’ approved production equipment?
Quite often the question comes up whether this or that piece of equipment is approved by authorities, or whether there are lists with approved equipment. Get the answer here.
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GMP News |
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Is there something like Authorities’ approved production equipment? |
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Quite often the question comes up whether this or that piece of equipment is approved by authorities, or whether there are lists with approved equipment. The question can be answered with a clear ‘No’. There are approvals for pharmaceutical products only, not for production equipment. Authorities or GMP guidelines neither allow equipment, nor do they forbid their usage (with the exception of filters emitting fibers). Here, companies have the freedom of choice but also the responsibility to use the equipment appropriate for their process or product. Standard equipment can be modified to fit best on the own process. GMP guidelines require that the selected equipment is suitable for the application and which can be sufficiently cleaned and maintained. Surfaces that have contact with in-process material or product are supposed to be non-reactive, additive, or absorptive to prevent that the quality decreases beneath the defined requirement. With regard to lubricants and synthetic/sealing materials this is different. The US FDA does not admit any seals, but has a white list of substances in their guidelines text they consider harmless. However, this merely means that these substances are not toxic in small quantities and therefore may be used. It does not imply their suitability for the own process or the proof of compatibility. For instance, EPDM is listed as sealant in 21 CFR 177.2600, but is not resistant in contact with oils or fats and may not be used in these cases. With regard to lubricants there is also a Positive list in the CFR, to which the components of a lubricant must be traceable. Alternatively, lubricants can be listed by the NSF in the so-called White Book. To do this, the NSF offers a registration procedure, which shows the toxicological safety. In addition there are organisations that may be of benefit for the selection of equipment or equipment parts. For example, the EHEDG checks and certifies the cleanability of equipment. The Fraunhofer IPA rates materials with respect to their cleanroom suitability. Here, cleanability, organic resistance, abrasion / particle emission and outgassing are examined. |
FDA Guidance for Industry: Electronic Source Data in Clinical Investigations
FDA Guidance for Industry: Electronic Source Data in Clinical Investigations
The FDA published its new Guidance for Industry (GfI) – “Electronic Source Data in Clinical Investigations” in September 2013. The Guidance defines the expectations of the FDA concerning electronic source data generated in the context of clinical trials. Find out more about this Guidance.
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FDA Guidance for Industry: Electronic Source Data in Clinical Investigations |
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After more than 5 years and two draft versions, the final version of the Guidance for Industry (GfI) – “Electronic Source Data in Clinical Investigations” was published in September 2013. This new FDA Guidance defines the FDA’s expectations for sponsors, CROs, investigators and other persons involved in the capture, review and retention of electronic source data generated in the context of FDA-regulated clinical trials. In an effort to encourage the modernization and increased efficiency of processes in clinical trials, the FDA clearly supports the capture of electronic source data and emphasizes the agency’s intention to support activities aimed at ensuring the reliability, quality, integrity and traceability of this source data, from its electronic source to the electronic submission of the data in the context of an authorization procedure. The Guidance addresses aspects as data capture, data review and record retention. When the computerized systems used in clinical trials are described, the FDA recommends that the description not only focus on the intended use of the system, but also on data protection measures and the flow of data across system components and interfaces. In practice, the pharmaceutical industry needs to meet significant requirements regarding organisation, planning, specification and verification of computerized systems in the field of clinical trials. The FDA also mentions in the Guidance that it does not intend to apply 21 CFR Part 11 to electronic health records (EHR). Author: Source: |
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.
Cleaning Validation
Cleaning Validation
Cleaning validation is primarily applicable to the cleaning of process manufacturing equipment in the pharmaceutical industry. The focus of cleaning validation is those cleaned surfaces that, if inadequately cleaned, could potentially contaminate the product subsequently manufactured in that same equipment.
This primarily covers product contact surfaces in the cleaned equipment. Cleaning validation is not performed only to satisfy regulatory authorities. The safety of patients is the primary objective, and product contamination presents serious liability issues for any pharmaceutical manufacturer or contract organization.
The history behind cleaning validation
The unhygienic conditions in Chicago’s meat- packing plants revealed in Upton Sinclair’s novel, “The Jungle”, allowed the government investigators and congress to enact the meat inspection law and the Pure Food and Drugs Act in 1906, the law forbade adulteration, misbranding adulteration, misbranding of foods, drinks, and drugs.
Thirty years later the drug tragedy “elixir of sulfanilamide” which killed over…
View original post 1,593 more words
cGMPs for Active Pharmaceutical Ingredient (API) and Excipient Production
EMA publishes final QP Declaration Template
EMA publishes final QP Declaration Template
The European Medicines Agency (EMA) has published the Template for the Qualified Person’s declaration concerning GMP compliance of the active substance used as starting material and verification of its supply chain – “The QP declaration template”.
Read more.
How to document a Product Transfer? Example templates!
| How to document a Product Transfer? Example templates! |
| All participants of the GMP training course “GMP-compliant Product Transfer” will receive a special version of the Guideline Manager CD including documents immediately useable for planning and documenting a site change. Read more. |
http://www.gmp-compliance.org/eca_mitt_4328_8427,8526_n.html
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How to document a Product Transfer? Example templates! |
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After the changes in chapter 4 of the EU GMP Guide have become effective, written procedures and documentation of the transfer activities are required. For example, a Transfer SOP, transfer plan and report have become mandatory this way. As a participant of the GMP education course “GMP-compliant Product Transfer” in Prague, from 7-9 October 2014 you will receive a special version of the Guideline Manager CD with a special section concerning product transfers. This section contains, amongst others, a Transfer SOP and a template for a Transfer Plan. Both documents are in Word format and can immediately be used after adoption to your own situation.
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India under Pressure: GMP Conformity Not Guaranteed in many APIs Facilities
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India under Pressure: GMP Conformity Not Guaranteed in many APIs Facilities |
| The pressure on India is getting bigger because of GMP deficiencies found during inspections. An article of the news agency Reuters summarised impressive information on the topic. Read more here about the Reuters article. |
read here
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India under Pressure: GMP Conformity Not Guaranteed in many APIs Facilities |
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The pressure on India is getting bigger because of GMP deficiencies found during inspections. A wide range of FDA Warning Letters and FDA Import Alerts are given special attention. The GMP deviations observed are extreme and partly alarming with regard to the potential risks for the patients. Even elementary GMP requirements have been neglected. Production areas were often found in an uncontrolled status (risk of cross contamination) that medicinal products had to be recalled. The Warning Letter for Wockhardt is one of the most prominent examples. According to an article published in RAPS Online, FDA inspectors wrote in this letter about the location: “a wide range of disturbing allegations, including bathrooms that allowed for the collection of standing urine on floors, products contaminated with glass and unknown “black particles,” staff that repeatedly lied to FDA on multiple occasions, and manufacturing lines that were kept hidden from investigators.” At the same time, this shows that effective and extensive GMP monitoring in India is inexistent. An article of the news agency Reuters summarised impressive information on the topic. According to it, 1,500 inspectors are responsible for 10,000 factories. In one out of every 22 samples, lack of quality has been observed. These data come from a study already performed two years ago. Reuters refers to industry analysts who say that companies which cannot deliver into the USA because of an Import Alert might continue their production and sell their products to other countries which are not aware of those GMP deficiencies. This is a terrifying scenario which is – according to experts’ statements – current practice in India. Such serious problems can only be explained because of totally insufficient monitoring of medicinal products in India. A GMP inspector in India told Reuters: “I took salaries for 30 years without doing anything. I visited some of the plants … not with the intention of taking any action, but just out of curiosity.” Reuters quotes an employee of India’s health ministry who says that only the US FDA complains about Indian factories. “(…) other countries have no problems with our drugs. They have never raised any objections or have found fault,” This statement can be easily refuted. The EudraGMDP database currently lists 38 facilities in India which have been classified as “GMP non-compliant” because of negative GMP inspections. The lack of adequate GMP supervision (GMP Inspections) by Indian Authorities also raises questions on the EU procedure to require Written (GMP) Confirmations from agencies around the world. In order to import an API from a manufacturer located outside the EU the legal provisions require that a Written Confirmation has to be issued by the exporting countries (only some countries like e.g. Switzerland, USA have been found to have equivalent GMP Inspection systems and do not need to issue Written Confirmations). India has published many Written Confirmations for API manufacturers in India. However, some of the companies who own a Written Confirmation received FDA Warning Letters or EU GMP non-compliance statements only some months after the Written Confirmations were issued. This questions the value of the Written Confirmations also for all other facilities in India not inspected recently by EU or FDA inspectors. The information published by Reuters, RAPS Online and other well recognized media sources may require to initiate additional actions by industry and regulators in the EU in order to safeguard APIs imported from India. |
Variations: How to submit Results of Confirmatory Stability Studies
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Variations: How to submit Results of Confirmatory Stability Studies |
| The Co-ordination Group for Mutual Recognition and Decentralised Procedures has revised the Q/A-List for the Submission of Variations adding a question and answer regarding the submission of the results of confirmatory stability studies on production-scale batches. Read more. |
read at
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Variations: How to submit Results of Confirmatory Stability Studies |
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As a part of the Heads of Medicines Agencies, the CMD(h) (Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human) is publishing a number of interesting documents. Best Practice Guides questions-and-answer documents give valuable information regarding the point of view of the European registration and supervisory authorities. Now, the Q/A-List for the Submission of Variations has been updated. Question 2.13 is dealing with the submission of the results of confirmatory stability studies on production-scale batches where stability data for pilot-scale batches have already been accepted during application for a MA. The answer is: Here you can find the document with tracked changes. The Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human, CMD(h), has been set up in the revised Pharmaceutical Legislation (Directive 2004/27/EC amending Directive 2001/83/EC) for the examination of any question relating to marketing authorisation of a medicinal product in two or more Member States in accordance with the mutual recognition procedure or the decentralised procedure. The CMD(h) has started its activities in November 2005 and replaced the informal Mutual Recognition Facilitation Group, which was in operation over 10 years, to coordinate and facilitate the operation of the mutual recognition procedure. |
New Drug Approvals 