QUALITY

A review of fungal contamination in pharmaceutical products and phenotypic identification of contaminants by conventional methods

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Article (PDF Available)inEuropean Journal of Parenteral and Pharmaceutical Sciences 17(1):4-19 · January 2011
Abstract
Microbial contamination of pharmaceutical products is one of the major reasons for product recall and manufacturing problems. Knowledge of the distribution of survival microorganisms in pharmaceutical environments is critical in the process control of non sterile and sterile pharmaceutical products. This knowledge is somewhat limited by the ubiquitous distribution of microorganisms in manufacturing facilities particularly fungal distribution. Identification of these fungi isolates from pharmaceutical environments using standard identification procedures requires experienced skilled technologists. To develop the proper corrective action when out of specification results are obtained, accurate fungal identification is needed if the contamination source has to be determined and tracked. Corrective action may not be effective if erroneous information is used to solve a given problem. This review provides guidance about knowledge of fungal contamination in pharmaceutical products and outlines an economic approach to phenotypic identification using conventional methods.

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].

https://www.researchgate.net/publication/275335972_A_review_of_fungal_contamination_in_pharmaceutical_products_and_phenotypic_identification_of_contaminants_by_conventional_methods

REFERENCES

http://shodhganga.inflibnet.ac.in/bitstream/10603/40641/5/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.

Fungal contamination risks

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/

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Tim Sandle

Microbiology, Biotechnology

PhD
Vijayakumar Rajendran

Vijayakumar Rajendran

Immunology, Biotechnology, Mycology

Ph.D

Drug Approval Strategies in the Age of Fast Track, Breakthrough Therapy and Accelerated Approval

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Process Validation and Regulatory Review

Drug Approval Strategies in the Age of Fast Track, Breakthrough Therapy and Accelerated Approval

To meaningfully discuss the process validation and regulatory approval strategies required for drugs that have been designated Fast Track, Breakthrough Therapy or Accelerated Approval drugs, we must first clarify these designations and briefly remind ourselves what the Process Validation guidance looks like. Then we will be able to clearly identify challenges and approaches to these barriers when working to bring a Fast Track, Accelerated Approval or Breakthrough Therapy drug to market.

Fast Track designation – Fast Track drugs treat serious conditions where there is an unmet medical need. Concluding that a condition is serious and that there is an unmet medical need most definitely leaves room for judgement, but generally speaking, the conditions these drugs treat are life-threatening, and the drug in question is expected to contribute to survival, daily functioning or the likelihood that a condition will advance to a very serious state. Fast Track drugs receive the benefit of more frequent meetings and communication with the FDA, and the drug qualifies for Accelerated Approval and rolling review of the Biologic License Application (BLA) or New Drug Application (NDA).

Breakthrough Therapy – Breakthrough Therapy status can be assigned to drugs that treat a serious condition when preliminary clinical data show significantly improved outcomes compared to treatments currently on the market. Breakthrough Therapies are eligible for: Fast Track designation benefits, extensive FDA guidance on effective drug development early in the development process and organizational commitment, including access to FDA senior managers.

Accelerated Approval – The FDA established accelerated approval regulations in 1992. Accelerated Approval could be given to drugs that met a serious unmet medical need, and approval was based on a surrogate endpoint. Fast forward to 2012 when Congress passed the Food and Drug Administration Safety Innovations Act (FDASIA). This amendment to the Federal Food, Drug, and Cosmetic Act (FD&C Act) allowed approval to be based on either a surrogate endpoint per the 1992 regulations or approval based on an intermediate clinical endpoint. For example, as a result of the 2012 legislation, a cancer drug could be approved based on the surrogate endpoint of increasing the probability of cancer to going into remission or the intermediate clinical endpoint of shrinking tumor size—an outcome that is strongly correlated with the ability to much more successfully treat cancer and induce remission.

These FDA designations are clearly designed to increase the availability and speed to market of drugs treating serious conditions where unmet medical needs exist. Given that nimbleness and speed has historically not been the pharmaceutical industry’s nor FDA’s strong suit—commercialization of a drug has historically taken on average 12 years and cost up to $2.5B (including expenditure outlays and opportunity costs). The ability for these designations to save both time and money is very attractive. However, given the slow-moving nature of the industry, changes in both mindset and approaches are needed by both drug innovators and regulators to validate processes and ensure drug quality within the faster-moving constructs.

Let’s now turn to the most recent Process Validation guidance so that we may juxtapose that system with the nimble needs of Fast Track Designation, Breakthrough Therapy and Accelerated Approval drugs—ultimately, making some observations regarding needed Process Validation and overall regulatory approval approaches as the industry moves towards accelerated development processes for an increasing number of drugs.

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WHAT IS PROCESS VALIDATION?
According to the FDA’s 2011 Process Validation (PV) guidance, “For purposes of this guidance, process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the lifecycle of the product and process.”

The Three Stages of Process Validation:
Stage 1: Process Design–manufacturing process is defined during this stage and is based on knowledge acquired through development and scale-up activities.

Stage 2: Process Qualification–process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.

Stage 3: Continued Process Verification–ongoing assurance during manufacturing that the process is controlled and the outcome predictable.

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Keys for Successful Validation Include:
• Gaining knowledge from the product and process development
• Understanding sources of variation in the production process
• Determining the presence of and degree of variation
• Understanding the impact of variation on the process and end product
• Controlling variation in a manner aligned with Critical Quality Attributes (CQA) and the risk a given attribute introduces to the process

Process Qualification, a key component of Process Validation, should be based on overall level of product and process understanding, level of demonstrable control, data from lab, pilot and commercial batches, effect of scale and previous experience with similar products and processes. Process Qualification is generally recommended to be based on higher levels of sampling, additional testing and greater scrutiny of process performance than would be typical of routine commercial production.

As we will now explore, some of the demands of Process Qualification and overall Process Validation is severely challenged by the approaches required when bringing a Fast Track, Accelerated Approval or Breakthrough Therapy drug to market.

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NOVEL APPROACHES NEEDED FOR ACCELERATED APPROVALS
Historically, it has taken an average of 12 years and, according to a Tufts Center for the Study of Drug Development (CSDD) report, including expenditures and opportunity costs, an average of ~$2.6 billion to bring a prescription drug to market. This paper will refrain from making editorial comments about this pharmaceutical industry fact; however, the undeniable reality is that the speed required at every point in the industry to develop Fast Track, Accelerated Approval or Breakthrough drugs is having a profound impact.

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Approval of a Breakthrough drug, which of course is classified for Accelerated Approval, means manufacturers need to develop Chemistry, Manufacturing and Controls (CMC) data in about half the time of the traditional process. In addition, Breakthrough designation does not mean the innovator company can do less. In order to meet these accelerated timelines, they do need to start analytical methods creation and product and process characterization sooner, and handle the process differently. Validation of a process traditionally has called for sufficient data and an adequate number of runs to convince the manufacturer (and regulators) that the process works. As we will explore below, Breakthrough therapies are often in the market before the product is fully validated.

However, the guiding force behind these new approaches is that despite sharply reduced timeframes, manufacturers cannot compromise patient safety or product supply. Therefore, characterization of critical product and process attributes is typically required much earlier in the process.

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Challenges and Realities of Process Validation and Regulatory Approval within the Accelerated Drug Paradigm:
• The collaboration and communication required between the FDA and innovator companies is extensive. Given limited FDA resources and extensive resources required by the organizations of innovator companies, is the growth of the Fast Track/Breakthrough Therapy/Accelerated Approval programs sustainable?
• New Drug Applications (NDA) for Breakthrough Therapies include less manufacturing information and data requiring alternative risk-mitigation approaches and often nontraditional statistical models.
• Both patient safety and product supply is at the forefront, without the data and historical knowledge traditionally used to address these concerns.
• The primary concerns for CMC reviewers include incomplete characterization of the drug, underdeveloped analytical methods and a lack of full understanding of a product’s Critical Quality Attributes (CQA) and associated risks.
• Process Validation will, in many cases, be incomplete at product launch.

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THE CHANGED PARADIGM RESTORED TO ORDER (SORT OF)
The “restored order” for the approval of, and ultimate Process Validation for, Breakthrough/Accelerated Approval drugs will not look like anything we normally see. Again, all Breakthrough and Accelerated Approval drugs address very serious conditions and offer treatment where none currently exists, or offers benefits well above and beyond drug products currently on the market. Therefore, flexibility has been applied to segments of the traditional product review and approval process to speed the availability of treatments for these critical conditions.

Despite the flexibility in, and often changes to the product review and approval process, patient safety remains at the forefront, as well as the guarantee of consistent product supply.

Approaches for Successfully Handling the Approval and Validation of Accelerated Approval Drugs:
• Open and transparent communication with the FDA is essential throughout the entire approval and post-market process. The pharmaceutical company mindset of not wanting to learn certain information for fear of needing to revalidate based on those discoveries has no place in this new reality. New information will be learned pre- and post-launch, and plenty of amendments will need to be filed.
• Given the compressed development timeframes, less stability data will be available at submission. Additional data will be submitted via amendments during the review cycle, and in some cases, post-market.
• Launch commercial process with limited experience and optimize post-approval–the classic three runs is not the guiding force within this construct. The level of flexibility regulators will extend is determined for each specific product. Factors taken into consideration include: riskiness of product characteristics, seriousness of the condition and medical need, complexity of manufacturing processes, state of the innovator’s quality system and merits of the innovator’s risk-based quality assessment including Critical Quality Attributes (CQA).
• Novel statistical models and approaches will need to be applied in many cases. Representative samples and assays for these models will likely need to be acquired from sources, like prior knowledge and use of comparability protocols. Also, determination of the appropriate use of stability data from representative pilot scale lots will be required.
• Manufacturers should freely acknowledge where data is limited, demonstrate that the missing data pose no risk to patient safety or product supply and outline post-market strategy for acquiring the missing data. Conversations with the FDA are clearly required for successful outcomes.
• Focus on patient safety and reliable supply of quality product at launch, not process optimization. In addition, begin critical product attributes and process characterization work much earlier than a typical pharmaceutical development process. In many cases, consider broader product quality ranges for non-Critical Quality Attributes until further manufacturing experience is acquired post-approval.

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Enhance analytical methods and understanding to offset more limited process understanding and to support future comparability work. Extremely important, involve commercial Quality Control representatives in the development assay design.
• Again, CMC activities that may be incomplete at launch include: Process Validation, stability studies on commercial product, manufacturing scale/tech transfer data and complete control system data.
• A post-approval product lifecycle management plan is a must, and it needs to be included in the filing to support deferred CMC activities.

Fast Track, Breakthrough Therapy and Accelerated Approval drugs have profoundly changed the thinking and approach to Process Validation and other CMC activities.

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Sources:
Joseph A. DiMasia, Henry G. Grabowskib, Ronald W. Hansenc, “Innovation in the Pharmaceutical Industry: New Estimates of R&D costs,” Tufts Center for the Study of Drug Development, Tufts UniversityJ. Wechsler, “Breakthrough Drugs Raise Development and Production Challenges,” Pharmaceutical Technology 39 (7) 2015.Earl S. Dye, PhD, “CMC/GMP Considerations for Accelerated Development and Launch of Breakthrough Therapy Products,” Roche“Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics,” U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), May 2014 ProceduralAnthony Mire-Sluis, Michelle Frazier, Kimberly May, Emanuela Lacana, Nancy Green, Earl Dye, Stephan Krause, Emily Shacter, Ilona Reischl, Rohini Deshpande and Joe Kutza, “Accelerated Product Development: Leveraging Industry and Regulator Knowledge to Bring Products to Patients Quickly,” BioProcess International, December 2014

Daniel Alsmeyer and Ajay Pazhayattil, Apotex Inc., “A Case for Stage 3 Continued Process Verification,” Pharmaceutical Manufacturing, May 2014

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/////////////Process Validation, Regulatory Review, Drug Approval Strategies,  Fast Track, Breakthrough Therapy, Accelerated Approval

Written Confirmation expired: Can an API still be imported when produced earlier?

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What needs to be considered if an API is produced in the time period of a valid written confirmation but imported after this confirmation has expired? This is answered in a revised Q&A Document of the EU Commission.

see………http://www.gmp-compliance.org/enews_05432_Written-Confirmation-expired-Can-an-API-still-be-imported-when-produced-earlier_15432,15354,15367,Z-QAMAP_n.html

The EU Commission has updated its Question and Answers Document “Importation of active substances for medicinal products for human use” (now version 7). In this updated version, the question “Can an API batch manufactured during the period of validity of a written confirmation be imported into the EU once the written confirmation is expired?”

In the answer it is referred to Article 46(b)(2)(b) of Directive 2001/83/EC, where it is defined that APIs can only be imported if they are manufactured in accordance with EU GMP or equivalent, and accompanied by a written confirmation from the competent authority of the exporting third country certifying this.

But what if an API is produced in the time period of a valid written confirmation but imported after this confirmation has expired?

In the respective answer the EU Commission states that “it is legitimate to consider that the guarantees of equivalence provided by the written confirmation apply to any API batch in the scope of the written confirmation which was released for sale within the period of validity of the written confirmation, even if not exported in that time period.”

So the answer is ‘yes’, it still can be imported. But it needs to be accompanied by the expired written confirmation together with appropriate documentation which proves “that the whole consignment has been manufactured and released for sale by the quality unit before the expiry date of the written confirmation” and “provides a solid justification of why a valid written confirmation is not available.”

An import without any written confirmation is not possible.

///////////API, produced, time period of a valid written confirmation, imported, confirmation has expired, revised Q&A Document of the EU Commission.

EDQM announces revision of general chapter Monocyte Activation Test (2.6.30)

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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.

see  http://www.gmp-compliance.org/enews_05440_EDQM-announces-revision-of-general-chapter-Monocyte-Activation-Test–2.6.30-_15500,15298,15853,15541,Z-MLM_n.html

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.

/////Monocyte Activation Test

ECA Visual Inspection Groups works on new FAQ Document

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The advisory board of ECA’s Interest Group for Visual Inspection is working on a revision of a document with frequently asked questions with regard to visual inspection of parenterals.

see

http://www.gmp-compliance.org/enews_05379_ECA-Visual-Inspection-Groups-works-on-new-FAQ-Document_15266,15265,15221,15160,Z-PEM_n.htmlregard to visual inspection of parenterals.

The webpage of ECA’s Interest Group for Visual Inspection contains several sources for giving advice in the field of visual inspection of parenterals. Besides the practical guidance paper, it contains an online discussion forum and a document with frequently asked questions. It has become clear though, that many of the questions in the forum recur and that these questions have already been answered in the FAQ document. It was therefore decided to restructure the FAQ document:  the questions will now be sorted by topic to make the document easier to read. Also, in a group survey in February 2016 everybody was asked to send additional questions. The advisory board is now working on selected new questions which will be added to the restructured questions & answers document. The revised document will contain the following elements:

  • Manual inspection
  • Automated inspection
  • Qualification/Validation
  • Test sets
  • Requalification
  • AQL Testing
  • Defect categorisation
  • Special products
  • Regulatory affairs

It is planned to finish the document in summer 2016, but at the latest during a face-to-face meeting at the next group event in September 2016 in Barcelona. It will be made available to all group members afterwards.

//////////ECA Visual Inspection Groups,  FAQ Document, visual inspection of parenterals,

APIs from Legitimate and Reliable Sources

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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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USP revises Chapter on Pharmaceutical Water

Posted on Updated on

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