FDA takes unprecedented step toward more efficient global pharmaceutical manufacturing inspections
The U.S. Food and Drug Administration has determined the agency will recognize eight European drug regulatory authorities as capable of conducting inspections of manufacturing facilities that meet FDA requirements. The eight regulatory authorities found to be capable are those located in: Austria, Croatia, France, Italy, Malta, Spain, Sweden and the United Kingdom. Continue reading.
A review of fungal contamination in pharmaceutical products and phenotypic identification of contaminants by conventional methods (PDF Download Available). Available from: https://www.researchgate.net/publication/275335972_A_review_of_fungal_contamination_in_pharmaceutical_products_and_phenotypic_identification_of_contaminants_by_conventional_methods [accessed Jun 12, 2017].
REFERENCES
Click to access chapter%202.pdf
Any pharmaceutical product, whether manufactured in the hospital or industrial environment, has the potential to be contaminated with microorganisms. With sterile products, any microbial contamination presents an unacceptable risk; with non-sterile products, the implication of the contamination is dependent upon whether the microorganism can be considered ‘objectionable’, and then to the extent that it can cause patient harm (and here a risk assessment is ordinarily required)1.
There are different types of microorganisms associated with product recalls. At this stage into the 21st century, fungal contamination of nonsterile products is one of the major reasons for product recalls, production shutdowns, and losses in labour and manufacturing. This can result in a reduced shelf life by compromising product integrity or present potential health hazard to patients2. Many of the reasons are due to the lack of quality control, process control and proper testing.
Most reports relating to the contamination of pharmaceutical products centre on bacterial contamination rather than fungi. The reasons for this may relate to few ‘microbiology’ laboratories in pharmaceutical organisations having trained mycologists; to an underestimation of the association between fungi and product contamination incidents; and due to a lack of appreciation of the risks that fungi can pose to cleanrooms and controlled environments3. This article considers some of these issues and, in doing so, argues that the contamination risk posed by fungi to pharmaceutical products is greater than the level of industrial and academic interest would suggest.
Fungi are more evolutionarily advanced forms of microorganisms, as compared to the prokaryotes (such as bacteria). Fungi are commonly divided into two distinct morphological forms: yeasts and hyphae (or filamentous). Yeasts are unicellular fungi which reproduce asexually by blastoconidia formation (budding) or fission4. Fungal contamination in pharmaceutical products represents a potential hazard for two reasons. First, it may cause product spoilage; the metabolic versatility of fungi is such that any formulation ingredient from simple sugars to complex aromatic molecules may undergo chemical modification in the presence of a suitable organism. Spoilage will not only affect therapeutic properties of the product but may also discourage the patient from taking the medication. Second, product contamination represents a health hazard to the patient, although the extent of the hazard will vary from product to product and patient to patient, depending on the types and numbers of organisms present, the route of administration, and the resistance of the patient to infection. https://www.europeanpharmaceuticalreview.com/24118/topics/microbiology-rmm/fungal-contamination-pharmaceutical-products-growing-menace/
The FDA draft guidance for combination products has a substantial impact on the development of Oral Inhalation and Nasal Drug Products (OINDPs) as it requires that the manufacturers have to be compliant not only with CGMPs for the drugs (21 CFR Parts 210 and 211) but also with the quality system (QS) regulations for devices (21 CFR Part 820). Find out more about the FDA Draft Guidance for Combination Products.
Based on the CGMP requirements for single-entity and co-packaged combination products (21 CFR Part 4) the manufacturers of Oral Inhalation and Nasal Drug Products (OINDPs) have to be compliant with CGMPs for the drug constituent part(s) (21 CFR Parts 210 and 211) and the quality system (QS) regulations for device constituent part(s) (21 CFR Part 820).
This can be achieved either by a drug CGMP-based streamlined approach (21 CFR 4.4(a)) or a QS regulation-based streamlined approach (21 CFR 4.4(b)). Following the first approach the combination product manufacturers have to be compliant with the drug CGMP and device QS regulation requirements:
– 21 CFR 820.20 – Management responsibility
– 21 CFR 820.30 – Design controls
– 21 CFR 820.50 – Purchasing controls
– 21 CFR 820.100 – Corrective and preventive actions
– 21 CFR 820.170 – Installation
– 21 CFR 820.200 – Servicing
The OINDP manufacturers have to be clearly stated in their submission and at the initiation of a pre-approval inspection (PAI) whether they are operating under the drug CGMP or QS regulation-based approach.
Here you can see the complete FDA Draft Guidance on Combination Products including the requirements for Oral Inhalation and Nasal Drug Products.
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ICH Q10 was published in its final version already in 2008. However, today many companies still have problems to understand how to implement ICH Q10 “Pharmaceutical Quality System” into practice. Quality Assurance and GMP are basic requirements which have been implemented for many years in the pharmaceutical industry (including the API industry). So what is needed to demonstrate that a Pharmaceutical Quality System has been implemented? Please read more about the GMP Questions and Answers.
ICH Q10 was published in its final version already in 2008. However, today many companies still have problems to understand how to implement ICH Q10 “Pharmaceutical Quality System” in practice. Quality Assurance and GMP are basic requirements which have been implemented for many years in the pharmaceutical industry (including the API industry). So what is needed to demonstrate that a Pharmaceutical Quality System has been implemented?
ICH offers a set of questions and answers which provide more details about the expectations. They were published in 2009 already but are not well-known by the industry. ICH writes: “When implemented, a company will demonstrate the use of an effective PQS through its documentation (e.g., policies, standards), its processes, its training/qualification, its management, its continual improvement efforts, and its performance against pre-defined key performance indicators (see ICH Q10 glossary on performance indicator). A mechanism should be established to demonstrate at a site how the PQS operates across the product lifecycle, in an easily understandable way for management, staff, and regulatory inspectors, e.g., a quality manual, documentation, flowcharts, procedures. Companies can implement a program in which the PQS is routinely audited in-house (i.e., internal audit program) to ensure that the system is functioning at a high level.”
The questions and answers document also states that there is no certification program in place for a Pharmaceutical Quality System. In addition, ICH provides information about how product-related inspections will differ in an ICH Q8, Q9 and Q10 environment. ICH writes: “In the case of product-related inspection (in particular, preauthorization) depending on the complexity of the product and/or process, greater collaboration between inspectors and assessors could be helpful (for example, for the assessment of development data). The inspection would normally occur at the proposed commercial manufacturing site, and there is likely to be greater focus on enhanced process understanding and understanding relationships, e.g., critical quality attributes (CQAs), critical process parameters (CPPs). The inspection might also focus on the application and implementation of quality risk management principles, as supported by the pharmaceutical quality system (PQS).”
In addition to ICH, regulatory authorities also provide further information. The British Authority MHRA, for example, answers the question: Should a company have a procedure to describe how it approaches QRM related to manufacture and GMP? The answer is: “Yes, the procedure should be integrated with the quality system and apply to planned and unplanned risk assessments. It is an expectation of Chapter 1 that companies embody quality risk management. The standard operating procedure (SOP) should define how the management system operates and its general approach to both planned and unplanned risk management. It should include scope, responsibilities, controls, approvals, management systems, applicability, and exclusions.”
The ECA Academy summarised the most relevant questions and answers from regulators like ICH, EMA, FDA etc in a GMP Questions & Answers Guide which allows readers of the document to search for certain GMP questions. A subject index at the beginning of the document lists the most frequent searched terms.
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On 23 June, the EDQM in Strasbourg announced the revision of the pharmacopoeial general chapter 2.6.30 on Monocyte Activation Test.
During the last two years, the chapters of the European Pharmacopoeia relating to the detection of Endotoxins and Pyrogens were successively updated or revised, e.g. 5.1.10. “Guidelines for Using the Test for Bacterial Endotoxins” or 2.6.8.” Pyrogens” (see Pharmeuropa – Comments concerning revised texts about Bacterial Endotoxins). There, amongst others, the EDQM announced that the chapter 2.6.8. now includes a reference to 2.6.30. “Monocyte Activation Test” as a potential replacement for the test for pyrogens.
Last week, the EDQM published the information that during its 155th Session held in Strasbourg on 21-22 June 2016, the European Pharmacopoeia (Ph. Eur.) Commission adopted a revision of the general chapter Monocyte Activation Test (2.6.30).
It has been a goal of the Ph. Eur. Commission since nearly 30 years to consider the goals of the European Convention (ETS 123) to protect vertebrate animals used for experimental and other scientific purposes and to minimise the number of animal testing in the revisions of their documents.
The Monocyte Activation Test (MAT) is used to detect or quantify substances that activate human monocytes or monocytic cells to release endogenous mediators which have a role in the human fever response. The MAT is suitable, after product-specific validation, as a replacement for the rabbit pyrogen test (RPT). The revision of 2.6.30 should lead to a further reduction in the use of laboratory animals. It includes the results of the consultation of industry representatives, academics, regulatory authorities and Official Medicines Control Laboratories.
The revised general chapter Monocyte Activation Test (2.6.30) will be published in the Ph. Eur. Supplement 9.2 and will come into effect in July 2017.
For more information, please see the EDQM announcement European Pharmacopoeia Commission adopts revised general chapter on Monocyte-activation test to facilitate reduction in testing on laboratory animals.
In this context, please pay attention to “Monocyte Activation Test – MAT – A Joint Workshop of the Paul-Ehrlich-Institut (PEI) and ECA” on 7. September 2016 at the Paul-Ehrlich-Institut in Langen, Germany.
During the last two years, the chapters of the European Pharmacopoeia relating to the detection of Endotoxins and Pyrogens were successively updated or revised, e.g. 5.1.10. “Guidelines for Using the Test for Bacterial Endotoxins” or 2.6.8.” Pyrogens” (see Pharmeuropa – Comments concerning revised texts about Bacterial Endotoxins). There, amongst others, the EDQM announced that the chapter 2.6.8. now includes a reference to 2.6.30. “Monocyte Activation Test” as a potential replacement for the test for pyrogens.
Last week, the EDQM published the information that during its 155th Session held in Strasbourg on 21-22 June 2016, the European Pharmacopoeia (Ph. Eur.) Commission adopted a revision of the general chapter Monocyte Activation Test (2.6.30).
It has been a goal of the Ph. Eur. Commission since nearly 30 years to consider the goals of the European Convention (ETS 123) to protect vertebrate animals used for experimental and other scientific purposes and to minimise the number of animal testing in the revisions of their documents.
The Monocyte Activation Test (MAT) is used to detect or quantify substances that activate human monocytes or monocytic cells to release endogenous mediators which have a role in the human fever response. The MAT is suitable, after product-specific validation, as a replacement for the rabbit pyrogen test (RPT). The revision of 2.6.30 should lead to a further reduction in the use of laboratory animals. It includes the results of the consultation of industry representatives, academics, regulatory authorities and Official Medicines Control Laboratories.
The revised general chapter Monocyte Activation Test (2.6.30) will be published in the Ph. Eur. Supplement 9.2 and will come into effect in July 2017.
For more information, please see the EDQM announcement European Pharmacopoeia Commission adopts revised general chapter on Monocyte-activation test to facilitate reduction in testing on laboratory animals.
In this context, please pay attention to “Monocyte Activation Test – MAT – A Joint Workshop of the Paul-Ehrlich-Institut (PEI) and ECA” on 7. September 2016 at the Paul-Ehrlich-Institut in Langen, Germany.
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APIs from Legitimate and Reliable Sources
1. Introduction
Counterfeit and sub-standard APIs are increasingly present. Not only are they a fact of non-compliance but also they form a serious and increasing risk for patient safety. Various initiatives have been taken such as the founding of the FDA Counterfeit Drug Task Force, the European Commission’s current “Public consultation in preparation of a legal proposal to combat counterfeit medicines for human use” and the WHO Program “IMPACT” (International Medical Products Anti-Counterfeiting Taskforce).
API =Active pharmaceutical ingredient (synonym: drug substance)
Counterfeit API =Active pharmaceutical ingredient for which source and/or quality are falsely represented on the label, on the certificate of analysis or otherwise
Rogue API =API that is counterfeit or severely, deliberately non-compliant.
This writeup focuses on the interaction between the API manufacturer and the medicinal product manufacturer and provides possible measures that may be taken by both partners in order to ensure only non-rogue APIs are used in the manufacture of medicinal products. The proposed measures are considered as elements out of a whole puzzle. A risk-based approach should be applied to determine the necessity and value of the individual proposals, alone or in combination. The document does not address in detail the vendor qualification process as it is taken for granted that APIs are only purchased from suppliers that have been thorough checked
API manufacturer= Active pharmaceutical ingredient manufacturer
Medicinal product manufacturer= formulation manufacturer
Supply Chain
A supply chain is actually a complex and dynamicsupply and demand network. A supply chain is a system of organizations, people, activities, information, and resources involved in moving a product or service from supplier to customer.
2. Supply Chain:
Agents, Brokers, Distributors, Repackers, Relabelers As a general principle, the shorter the supply chain, the more secure it will be. This is reflected in the EU GMP Guidelines, Part 1 (5.26) specifying that starting materials (APIs, excipients) should be purchased, where possible, directly from the producer.
In addition to the length of the supply chain, any changes on the original container – e.g. by repackaging, relabeling – should be considered as an additional risk for alteration and should therefore, whenever possible, be avoided.
There is no doubt that the entire supply chain needs to be assessed from a quality perspective, covered by an effective supplier qualification program and the same principles as described in the following sections for the direct supply form API manufacturer to drug product manufacturer should be applied. This already starts at the point of selecting the contractor for transportation of the API (see also ICH Q7, 10.23).
3. On Site Visits / Audits
3.1.
Visits
A thorough knowledge of the supplier is a key element. Therefore, a close and stable relationship between the manufacturer of the API and the drug product manufacturer should be achieved by using various means of contact. A regular exchange between 3/8 sourcing- and purchasing people and the supplier contributes to strengthening this relationship, especially if the contact also includes regular visits on site. Site visits should not be restricted to the manufacturing site alone; intermediaries in the supply chain should be covered as well. It should be ensured that representatives of the purchasing department have a good GMP- and regulatory awareness and technical understanding so that these visits are as beneficial as possible, also in relation to compliance.
Audits=Auditing refers to a systematic and independent examination of books, accounts, documents and vouchers of an organization to ascertain how far the statements present a true and fair view of the concern.
3.2. Audits
An audit is considered the most effective way of verifying concrete and compliant manufacturing incl. distribution of APIs. However, apart from the fact that an audit is very time-consuming it only provides a snapshot of the situation and there is no 100% guarantee that evidence for any occurring counterfeiting activities may be identified. Nonetheless, there are various elements in a quality audit that may increase that probability and that respectively may confirm the reliability of the manufacturer.
Counterfeiting activities= To counterfeit means to imitate something. Counterfeit products are fake replicas of the real product. Counterfeit products are often produced with the intent to take advantage of the superior value of the imitated product
3.2.1 General
Whenever possible, the audit should be executed when an actual production campaign is ongoing.
Requests for changing the agenda at short notice during the audit, e.g. revisiting areas on another time or day, may be a useful approach to confirm the consistency of operations on site.
Warehouse=A warehouse is a commercial building for storage of goods. Warehouses are used by manufacturers, importers, exporters, wholesalers,transport businesses, customs, etc
3.2.2 Warehouse
The walk-through in the warehouse supports the verification of the materials management capability with respect to claimed annual production of the API and storage capacity.
Checking for the presence of intermediates or APIs in the warehouse that have been purchased and could be subject for relabeling or of APIs intended to undergo a reprocessing may lead to the identification of different sources of materials than claimed. The list of approved vendors should also be reviewed for this purpose.
The review of the materials management system and material movements (booking in/out) of concerned API starting materials, intermediates and the final API is another possible source of information in the warehouse. However, confidentiality with respect to other customers’ names needs to be respected.
Production=the action of making or manufacturing from components or raw materials, or the process of being so manufactured.
3.2.3 Production
The walk-through in production should cover the verification of the necessary equipment and necessary utilities by cross-checking with the production instruction and/or process flow chart.
Document Review=Document review (also known as doc review) is the process whereby each party to a case sorts through and analyzes the documents and data they possess (and later the documents and data supplied by their opponents through discovery) to determine which are sensitive or otherwise relevant to the case
3.2.4 Document Review
The review of master production instructions as well as analytical methods and specifications for raw materials, intermediates and the API as well as of executed documents/raw data and cross-checks with the regulatory document (e.g. DMF, CMC section, CEP dossier) is an important element in verifying regulatory compliance.
One can also verify the availability of production records and/or analytical raw data as well as retained samples (where applicable) of raw material, intermediates and API batches for specific batches that were either identified from the review of the stock cards/materials management system, product quality review or from supplied batches.
The timely and sequential correlation of equipment use logbooks in production and QC laboratory, production batch records (incl. electronic raw data), cleaning records and analytical raw data (incl. date/time on equipment printouts such as balances, chromatographic systems etc.) is a good indicator for on site production.
The review of the documentation related to seals (specifications – testing/approval according to specifications – reconciliation documentation – authorized persons identified and documented…) may be added.
A spot wise review of analytical raw data from stability studies (not only the summary table) as well as of the logbook of the stability chambers (e.g. date of sample in/out) and the check for physical availability of the stability samples should be included.
The adequate involvement of the drug product manufacturer in case of changes that can impact the quality and/or regulatory compliance of the API may be verified by the reviewing the history of changes and individual change request cases related to the production and testing of the API (incl. intermediates, raw materials),
4. Supporting Documentation
The availability of certain documents that are regularly available and up-dated, where applicable, may be considered as one efficient element in the continuous supplier monitoring process.
Inspections=Inspections are usually non-destructive. Inspections may be a visual inspection or involve sensing technologies such as ultrasonic testing, accomplished with a direct physical presence or remotely such as a remote visual inspection, and manually or automatically
4.1 Inspections,
Inspection history As part of the initial evaluation of a potential API supplier the GMP inspection history, with respect to inspecting regulatory body, inspection date, inspected areas (as far as this information is / is made available) and the inspection results should be reviewed. A regular up-date of the inspection history as part of the supplier monitoring and requalification process should be performed. On the other hand, as these inspections are not mandatory for APIs e.g. used in medicinal products for the EU, the non-availability of an inspection history may not lead to the conclusion that this API supplier is less reliable. 5/8
GMP=Good manufacturing practices (GMP) are the practices required in order to conform to the guidelines recommended by agencies that control authorization and licensing for manufacture and sale of food, drug products, and active pharmaceutical products. These guidelines provide minimum requirements that a pharmaceutical or a food product manufacturer must meet to assure that the products are of high quality and do not pose any risk to the consumer or public.
4.2 GMP certificates
GMP certificates of the API manufacturer, where available (see 4.1), should be provided, ideally as authentic copies.
Certificate of Analysis=A Certificate of Analysis is a document issued by Quality Assurance that confirms that a regulated product meets its product specification. They commonly contain the actual results obtained from testing performed as part of quality control of an individual batch of a product.
4.3 Certificate of Analysis
A thorough review of Certificate of Analysis, against regulatory documents (e.g. DMF, CMC section, CEP dossier) and in-house specification respectively, and with respect to GMP compliance (ICH Q7, 11.14) should be performed as part of incoming release testing of APIs. Suppliers involved in counterfeiting could apply improper documentation practices. In case of agents, brokers etc. being involved in the supply chain it is recommended to insist on a certificate of analysis issued by the original manufacturer of the API (see also 2.). Where a new certificate of analysis is prepared by agent, broker, distributor, there should be a reference to the name and address of the original manufacturer and a copy of the original batch Certificate should be attached, as specifically required by ICH Q7 11.43, 44
4.4 Certificate of Compliance,
Compliance Commitment A certificate of compliance issued by the API manufacturer, either as a separate document or as part of the certificate of analysis, which certifies that a specific batch has been manufactured according to ICH Q7 GMP requirements and in line with the applicable Registration Documents can provide additional assurance related to the awareness of the manufacturer on the quality and regulatory expectations of the customers.
4.5 On-going stability program
A GMP compliant manufacturer has an on-going stability program for its APIs (ICH Q7, 11.5). At least one batch of the API manufactured per year is added to the stability program and tested at least annually. A regular up-date of the program provided by the API manufacturer, not necessarily including stability data, gives additional assurance for actual and compliant systems.
4.6 Product Quality Review
The major objective of the Product Quality Review (ICH Q7, 2.5) is to evaluate the compliance status of the manufacture (process, packaging, labelling and tests) and to identify areas of improvement based on the evaluation of key data. It includes a review of critical in-process controls and critical API test results, of batches that failed to meet specification, of changes carried out, of the stability monitoring program, of quality-related returns/complaints/recalls and of the adequacy of corrective actions. Due to the comprehensive information included, the Product Quality Review provides a good overview of the manufacture of a certain API.
The document should be reviewed during an audit or as a minimum an approved executive summary should be made available by the API manufacturer.
4.7 Quality Agreement
The quality agreement as a tool to clearly define the GMP responsibilities strengthens the awareness of liabilities of both partners. The extent and level of detail of the agreement may vary and can depend on the material supplied, e.g. generic API versus exclusively synthesized API, but it should at least address – name of the product – mutually agreed specification (if not covered by supply agreement) – manufacturing site – applicable cGMP standards, e.g. ICH Q7 – compliance with the DMF or with other registration documentation – GMP audits related to the API (e.g. 3rd party auditing) – documents to be provided by the manufacturer, e.g. certificate of analysis, certificate of compliance, inclusion of copies of respective master documents may be addressed – arrangements for transportation and transport packaging (see 5.), e.g. description and degree of tampering proof seal to be used, inclusion of a copy of the master drum label may be considered – deviation handling – handling of and response to complaints – change management: involvement of the customer with respect to notification and approval – list of approved signatories may be included
5 Packaging:
labeling, tamper-proof sealing If the API manufacturer provides examples/templates of master labels, which he uses to label the containers, this supports the drug product manufacturer in identifying any manipulation on the material on its way from the manufacturer to the recipient.
The use of tamper-resistant packaging closure by the manufacturer provides additional assurance that the material was not adulterated on its way from the manufacturer to the drug product manufacturer. A manufacturer-specific design of the seal is recommended to be used; the use of unique seals may be considered. The communication of the type of seal, by the manufacturer to the user, completes the information chain.
Material Inspection = Critical appraisal involving examination, measurement, testing, gauging, and comparison of materials or items. An inspection determines if the material or item is in proper quantity and condition, and if it conforms to the applicable or specified requirements. Inspection is generally divided into three categories: (1) Receiving inspection, (2) In-process inspection, and (3) Final inspection. In quality control (which is guided by the principle that “Quality cannot be inspected into a product”) the role of inspection is to verify and validate the variance data; it does not involve separating the good from the bad.
Sampling= Sampling is the process of selecting units (e.g., people, organizations) from a population of interest so that by studying the sample we may fairly generalize our results back to the population from which they were chosen.
6. Material Inspection, Sampling, Analysis, Impurity Profile
At the point of receipt the first relevant action is to carefully perform the visual inspection of all the containers of the API. Attention shall be paid to the integrity and type of the sealing as well as to the special attributes added by the manufacturer (see above 4.7, 5.) such as label design, seal number and design.
The applied sampling regime related to the number of containers sampled, number of samples taken per container, analysis of individual and/or pooled samples as well as the extent of analysis, varying from identity test to full analysis may influence the probability of identifying counterfeiting, provided it may be identified by analytical means.
A risk-based approach, considering the qualification status of the supplier, may be chosen to define the extent of sampling and testing, considering the requirements for drug product manufacturers (e.g. Annex 8 to EU GMP Guidelines). 7/8 The impurity profile is normally dependent on the production process and origin of the API. The comparison of the impurity profile of a current batch with either previous batches or data provided by the manufacturer (e.g. as part of the regulatory submission) may help in order to identify changes related to modifications in the production process and may indicate whether the API might originate from a different manufacturer than the supposed one.
It is recommended to check the current (im)purity profile and compare it with former quality in regular intervals, at least once a year
DISCLAIMER
I , Dr A.M.Crasto is writing this blog to share the knowledge/views, after reading Scientific Journals/Articles/News Articles/Wikipedia. My views/comments are based on the results /conclusions by the authors(researchers). I do mention either the link or reference of the article(s) in my blog and hope those interested can read for details. I am briefly summarising the remarks or conclusions of the authors (researchers). If one believe that their intellectual property right /copyright is infringed by any content on this blog, please contact or leave message at below email address amcrasto@gmail.com. It will be removed ASAP
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Should Equipment Status Identification Labels be retained with the Batch Record?
Keeping equipment status identification labels with the batch record provides additional confirmation during the review process. But is it required?
Keeping equipment status identification labels with the batch record or other files is often done to provide additional confirmation during review of the record. It supports verification that certain equipment was cleaned before usage for manufacturing. But is it required?
The U.S. Food and Drug Administration FDA has answered this question in an Q&A Document. Assuming each major piece of equipment has a unique “Cleaning and Use Log” that is adequately retained, these “quick reference” equipment labels can be discarded according the agency. FDA sees “no value in the retention of such labels in addition to the required equipment log or batch record documentation. The labels serve a valuable, temporary purpose of positively identifying the current status of equipment and the material under process. Any status label should be correct, legible, readily visible, and associated with the correct piece of equipment. The information on the temporary status label should correspond with the information recorded in the equipment cleaning and use log, or the previous batch record for non-dedicated equipment.”
However, as said before, it might be useful keeping these labels in a batch record. Many companies are doing so; not because it is a requirement but it is a helpful and reliable practice.
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Changes to the fundamental monograph on pharmaceutical water <1231> Water for Pharmaceutical Purposes from the US-American Pharmacopeia have been published for comments in the Pharmacopeial Forum 41(5). The revision presented in the current draft mainly has a structural nature. The content of the monograph has been reorganised in 9 new chapters which aim at improving readibility and searchability of the content searched:
1. INTRODUCTION
2. SOURCE WATER CONSIDERATIONS
3. WATERS USED FOR PHARMACEUTICAL MANUFACTURING AND TESTING PURPOSES
4. VALIDATION AND QUALIFICATION OF WATER PURIFICATION, STORAGE, AND DISTRIBUTION SYSTEMS
5. DESIGN AND OPERATION OF PURIFIED WATER AND WATER FOR INJECTION SYSTEMS
6. SAMPLING
7. CHEMICAL EVALUATIONS
8. MICROBIAL EVALUATIONS
9. ALERT AND ACTION LEVELS AND SPECIFICATIONS
The draft document is available for free on the website of the USP Pharmacopeial Forum. You only need to register for free. The deadline for comments is 20 November 2015.
http://www.gmp-compliance.org/enews_5070_USP-revises-Chapter–1231–on-Pharmaceutical-Water_n.html
Drug Master File Procedures in the EU, the US and Japanhttp://www.gmp-compliance.org/daten/seminarpdf/ECA_DMF_2015.pdf
Speakers
Marieke van Dalen, Aspen Oss B.V, The Netherlands
Dr Hiltrud Horn, Horn Pharmaceutical Consulting, Germany
Dr Usfeya A Muazzam, Bonn, Germany
Dr Boris Pimentel, DSM-Nutritional Products AG, Switzerland
Dr Wilhelm Schlumbohm, Berlin, Germany
Learning Objectives
This education course is intended to provide guidance on the procedures for the European ASMF, the US-DMF and the Japanese DMF. You will get to know
how to describe manufacturing processes
how to compile data for drug substance stability, impurities and residual solvents
which are the important points to consider for US-DMFs
which are the requirements for Japanese DMFs
how to handle changes in European, US and Japanese DMFs
Participants will have the opportunity to take part in one of two parallel workshops about
Description of the manufacturing process or How to compile data for Impurities and Residual Solvents
Background
Documentation of the drug substance quality is an integral part of any marketing authorisation application. In Europe the most common document for this purpose is the Active Substance Master File (ASMF) as long as the applicant has no Certificate of Suitability of the pharmacopoeial monograph (CEP). The European ASMF procedure differs significantly from the US-DMF procedure and for strategic reasons it is very important to take these differences into account. Moreover there are particular requirements for DMFs in Japan. For global acting companies it is a big challenge to handle the different procedures of compiling, submitting, changing and maintaining Drug Master Files in an efficient way.
Target Group
The education course is designed for all persons involved in the compilation of pharmaceutical dossiers for marketing authorisations especially for Drug Master Files who want to become familiar with the different DMF procedures. Furthermore, the course will be of interest to personnel from Quality Units of the pharmaceutical and the API industry.
Programme
The European Active Substance Master File procedure – An Introduction
Chemical pharmaceutical documentation for active substance(s) –
Regulatory requirements in EU, USA
Types of active substances – types of documentation
CTD Module 3, CEP and ASMF (former DMF)
CEP for a substance for TSE risk assessment
Drug Master File Procedures in the US
Types of Drug Master Files
Submissions to DMFs
Closure of a DMF
US vs EU DMF – differences in the procedure
How to document drug substance stability
Stability Guidelines
Stability Testing of new drug substances and drug products
Storage Conditions
Bracketing and Matrixing Designs
Stability data from new drug dosage forms
How to document evaluation of stability data
Optimising the submission
Residual solvents and Impurities: synthesis derived Impurities, Metals and genotoxic Impurities
Guidelines
Impact of the new guidelines ICH Q3D and ICH M7
Sources of Impurities
Setting and justification of specifications
Residual solvents, solvent classes
Content and scope of data – documentation requirements
Frequent mistakes
Handling Changes in European Drug Master Files
Why is there a need for changes
Types of changes
How to communicate with the customers and how to get feed back
Differences between ASMF and CEP
How to maintain an ASMF
Keeping track of the customers’ stand in relation to a specific change
Handling Changes in US Drug Master Files
Post approval activities
Reporting requirements to the FDA (CBE 0, CBE 30, Annual Report)
Post approval commitments and post approval reporting requirements
Risk evaluation and mitigation strategies (REMS)
Major re-organisation of a US-DMF
Holder obligations
Requirements of the Drug Master File Procedure in Japan
Regulatory procedures in Japan
points to consider when dealing with Japanese authorities
Regulatory documentation standards
Master File registration procedure
Master File review by Japanese authority
Changes and Maintenance of Japanese Drug Master Files
Change procedures and communication with the Japanese authority
Types of changes
Notification of changes
Tel.: +49 (0)6221 / 84 44 0 E-Mail: info@concept-heidelberg.de
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| FDA issues Guidance for a clear Identification of pharmaceutical Companies |
| In November the US FDA has issued a Guidance for a clear identification of pharmaceutical companies. The authority now definitely prefers the DUNS system. Get more information. |
In our GMP News from September 2013 you learned about a draft of a FDA Guidance for Industry entitled “Specification of the Unique Facility Identifier (UFI) System for Drug Establishment Registration”. This document’s goal was to clearly identify pharmaceutical sites. The draft comprised (manageable) five pages – including the cover page. And in terms of volume this didn’t change. However, some of the alternatives still mentioned in the draft, are not stated any longer – as one can find out when contacting the authority in these cases. The method now wanted is a registration by a D-U-N-S- (Data Universal Numbering System) number. This number – which is a 9-digit code – is supplied by the company Dun & Bradstreet.
To find out more please see the complete Guidance for Industry “Specification of the Unique Facility Identifier (UFI) System for Drug Establishment Registration“.
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In the following News, you will find questions on pharmaceutical water preparation and distribution frequently asked during our courses, as well as their respective answers. Read more here.
During our courses and conferences participants quite frequently raise questions on pharmaceutical water preparation and distribution. Therefore following you will find some of these questions and their respective answers.
Question 1: Which concentrations of ozone are required in water systems?
The technical literature delivers different information about the ozone concentrations in water systems: e.g. ISPE Baseline Water and Steam: 0.02 ppm – 0.2 ppm; Collentro, Pharmaceutical Water: 0.2 ppm – 0.5 ppm and W.Setz, Ciba-Geigy 1990: max 0.04 ppm, for sanitisation 0.05 ppm.
The indications provided by the ISPE Baseline refer to the concentration required to prevent microbial growth. One can thus assume that a concentration of 20 ppb ozone can prevent any growth.
If systemic protection is desired i.e. the constant presence of ozone in the water, lower ozone values are sufficient.
In practice, approx. 0.02 to 0.05 ppm should be sufficient for Aqua Purificata. For sanitisation, it naturally depends on the sanitation time intervals – daily or weekly. Finally, the required ozone concentration for the system should be determined within the framework of the validation for the whole system.
Question 2: How many ozone measurement points should be available in the water system?
If ozone is used for the sanitisation of the distribution system, the effect should also be proven by means of – indirectly – the determination of the KBE values on the one hand, and on the second hand through the proof that the ozone concentration is measured at the appropriate points in the water system. For this purpose, the ISPE Baseline mentions at least 3 measurement points:
The measurement in the storage tank shows that the concentration is sufficient during the permanent ozonisation. After the UV system, a measurement is done to assure destruction of the ozone. The post-use point in the return flow of the pipeline system is measured to prove that the ozone concentration is sufficient during sanitisation.
Question 3: Is there – from a GMP point of view – a preferred sanitisation method?
Basically, the following three sanitisation procedures are used today:
The FDA, as well as the ISPE in its Baseline – are in favour of thermal sanitisation with steam. The Guidance for Industry: Sterile drug products produced by aseptic processing Prepared by Task Force (Japan) contains the following note:
“Since water for injection needs to be microbiologically pure, the equipment used for its production should be capable of withstanding periodic sterilization with pure steam at temperatures over 121°C for a given length of time. If steam sterilization is not possible because of low heat tolerance, an alternative sterilization or sanitization procedure (e.g., hot water or chemical agents) should be used for the equipment.”
GMP doesn’t specify any method. According to the state of the art, one should prefer sanitisation with steam.
Question 4: Is cold storage allowed in WFI systems?
For WFI and purified water, different temperatures are used. WFI is usually stored under heat.
In FDA’s Guide to Inspections of High purity Water Systems you can find two indications of temperatures which are actually contradictory. The first temperature interval is described under “System Design”. “The fist chapter basically states under “System Design” that it is recognized that hot water systems (here to understand as 65 to 80°C systems) are self sanitizing. Another temperature interval is indicated in the chapter “Piping”. This concretely means here that the Guide applies to hot 75 – 80°C circulating systems. These indications are in connection with the 6D rule:
FDA – GUIDE TO INSPECTIONS OF HIGH PURITY WATER SYSTEMS
“One common problem with piping is that of “dead-legs”. The proposed LVP Regulations defined dead-legs as not having an unused portion greater in length than six diameters of the unused pipe measured from the axis of the pipe in use. It should be pointed out that this was developed for hot 75 – 80°C circulating systems.”
It follows from the above that cold systems for WFI actually don’t comply with the requirements. Under these circumstances, it is likely that at least the FDA doesn’t accept cold WFI systems.
If appropriate measures (system design and sanitisation measures) can ensure that microbial growth is prevented, cold storage could basically be used. Different limits for cold storage can be found in guidelines and standards (Wallhäuser: 4°C; ISPE: 4° to 10°C). A sanitisation concept for cold storage determined within validation is imperative and should also consider the increased high-risk of bio film formation.
Question 5: Are sterilizing filters permitted in water systems?
The answer to that question requires the examination of the legal provisions and the standards and guidelines on the topic “Water”. The EU GMP Guide describes in a few points the requirements for facilities and equipment. Relating to the sterilizing filters, the following indications may be authorised:
In almost all guidelines, references are made to sterilizing filters. As an example, see the following statement from a Japanese guideline: Sterile drug products produced by aseptic processing (Japan 2006)
“As a rule, sterilizing filters should not be placed at water use points since the filters could mask microbiological contamination in the water system. Endotoxins could also be released from dead microorganisms retained in the filters. If the use of filters is unavoidable, the interval of replacement should be based on validation results.”
In this Japanese document, the position to filters is obvious: no sterilizing filters should normally be used. Yet, there can definitely be exceptions. The filters shouldn’t serve for masking too high KBE values. Finally, one should justify the use of such a filter.
Editor’s note: The following article is a follow up to a previous AlterNet piece about drugs whose dangerous side-effects emerged only after the pharmaceutical industry’s patents ran out.
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