FDA warns patients and doctors about risk of inaccurate results from home-use device to monitor blood thinner warfarin

FDA warns patients and doctors about risk of inaccurate results from home-use device to monitor blood thinner warfarin

The U.S. Food and Drug Administration today is warning patients and doctors, who use at-home or in-the-office medical devices to monitor levels of the blood thinner, warfarin, that certain test strips used with the devices may provide inaccurate results and should not be relied upon to adjust the drug dosage. Roche Diagnostics issued a voluntary recall of certain test strip lots used with its CoaguChek test meter devices. The recall involves more than 1.1 million packages of CoaguChek XS PT Test Strips that were distributed nationwide from Jan. 12, 2018 to Oct. 29, 2018. Today, the FDA announced this action as…Continue reading 

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624904.htm?utm_campaign=11012018_PR_FDA%20warns%20of%20inaccurate%20test%20results%20for%20device%20to%20monitor%20warfarin&utm_medium=email&utm_source=Eloqua

 

November 1, 2018

Release

The U.S. Food and Drug Administration today is warning patients and doctors, who use at-home or in-the-office medical devices to monitor levels of the blood thinner, warfarin, that certain test strips used with the devices may provide inaccurate results and should not be relied upon to adjust the drug dosage. Roche Diagnostics issued a voluntary recall of certain test strip lots used with its CoaguChek test meter devices. The recall involves more than 1.1 million packages of CoaguChek XS PT Test Strips that were distributed nationwide from Jan. 12, 2018 to Oct. 29, 2018. Today, the FDA announced this action as a Class I recall, the most serious type of recall, which means use of these devices may cause serious injuries or death.

The FDA is warning patients and health care professionals that they should not rely on these test meter devices to monitor warfarin levels if they’re using test strips affected by the recall. Instead, they should have blood drawn from a vein and have their levels measured by a laboratory test or use an alternative meter device.

“These strips are widely used and we are working diligently to warn health care providers and the public about the dangers associated with this recall. Using faulty strips can lead to serious errors in medication dosage that could cause serious harm or death in some patients,” said Jeffrey Shuren, M.D., director of the FDA’s Center for Devices and Radiological Health. “We are also working with the company on the swift removal of the recalled strips and to ensure the new corrected strips are distributed to patients and health care providers as quickly as possible.”

Millions of Americans take the blood thinner warfarin (also known by the brand names Coumadin and Jantoven) to prevent and treat blood clots. The drug may be prescribed for patients with certain types of irregular heartbeats, blood clots in the legs or lungs, or certain medical device implants such as artificial heart valves. Achieving the correct warfarin dosage is crucial, and patients need regular monitoring to test how long it takes their blood to clot. The response is measured by a blood test to check the International Normalized Ratio, or INR. This test can be performed by an accredited laboratory on blood drawn from a vein or with a fingerstick blood draw using an INR test meter at home or in a doctor’s office.

The FDA’s warning concerning the CoaguChek XS PT Test Strips is based on medical device reports submitted by Roche Diagnostics to the agency indicating that the test strips may provide results that are higher than the actual INR. As a result of incorrect INR results, some patients may be prescribed an insufficient warfarin dose or instructed to interrupt warfarin use, which may increase the risk for dangerous blood clots. Approximately 90 medical device reports and two serious patient injuries involving strokes were reported to the FDA.

Incorrect INR results are of particular concern for individuals at an increased risk of blood clots including those with mechanical heart valves, atrial fibrillation (irregular heartbeat) who are at a high risk of stroke, or those who had a recent blood clot. It is important to note that problems with the CoaguChek XS PT test strips are not likely to be evident to the patient.

Roche Diagnostics attributes the cause of the problem to a recent re-calibration of the test strips to a different international standard that occurred earlier this year. They plan to provide new batches of re-calibrated test strips, based on the previous international standard, to their customers by the end of November; the FDA reviewed validation data submitted by the company for these recalibrated strips. The test strips are used with the CoaguChek XS plus, CoaguChek XS Pro, CoaguChek XS professional, CoaguChek XS PST and CoaguChek Vantus test meter devices.

Patients who are using CoaguChek meters should contact their health care provider to get information about alternative test methods and to address questions regarding their individual testing schedule. Patients should also contact their patient self-testing service providers to find out when they will be getting their corrected test strips. Health care providers and patients may contact Roche Diagnostics to learn more details about the recall.

All health care providers, patients and caregivers, are strongly encouraged to voluntarily report INR test meter problems directly to the FDA through MedWatch, the FDA’s voluntary reporting program. Problems should be reported whenever one suspects that there may be an issue with an INR test meter such as a malfunction or incorrect result, or that the meter caused or contributed to a serious injury or death.

The FDA is committed to continuing to communicate publicly on this issue and will provide updates related to this recall when available.

//////////////////

Advertisement

Normal Operating Range (NOR) and Proven Acceptable Range (PAR)

In June of this year, the EMA issued a revision of their earlier Q&A document focused on NORs, PARs, and DSp.(2) First issued in draft form in 2015, this has been revised based on feedback and consultation with industry. The document focuses on five questions, which are summarized below along with a reflection on the answer provided and its implications.

1. What is a Normal Operating Range (NOR) and how should NORs be presented in the marketing authorisation dossier?

Answer: NOR is not an established ICH term. The NOR describes a region around the target operating conditions that contain common operational variability (variability that can’t always be controlled). A NOR can be established for several process parameters of the same process step, with the understanding that the NOR does not represent deliberate adaptation of the process, and that the NOR does not cover a parameter range that affects the quality of the process output. Otherwise, a PAR or a multivariate Design space should be established. The use of NORs alone is not intended to introduce flexibility in the conditions for manufacturing but to better quantify the actual uncontrollable operational variability of process parameters. NORs should therefore be presented in marketing authorisations as what is practically achievable.

Requests to provide details of NORs have become an increasingly prevalent request from reviewers, predominantly in Europe, the absence of such information being classified as a deficiency. It was noted that the term NOR seemed to have risen to prominence even though this it is not an ICH term. Interestingly the answer draws specific attention to this and concedes this is not a formal ICH term. The framing of this question is interesting and already indicates the EMA thinking by posing the question—how should NORs be presented? the subsequent answer makes very clear NORs should be presented. Is this an issue? Arguably not as many organizations have presented NORs within section S2.2 without challenge. But it makes abundantly clear that this is unlikely to be optional.

So what is an NOR? The document provides the following definition:

An NOR describes a region around the target operating conditions that contain common operational variability (variability that cannot always be precisely controlled to a single and specific value). This is consistent with the thinking of many and should allow the definition of a range which reflects equipment capability. For example, a range of 35 °C ± 5 C° may reasonably be considered an NOR given the variability of the temperature control and calibration systems.

Overall while effectively introducing a “new” term this is an established concept already widely used and thus this is not considered as a significant concern.

What Is a Proven Acceptable Range (PAR) and How Should PARs Be Justified and Presented in the Marketing Authorization Dossier?

---

Again a specific definition is provided:

The PAR is defined as a characterized range of a process parameter for which operation within this range, while keeping other parameters within set points or NORs, will result in producing a material meeting relevant quality criteria (ICH Q8 R2).(1)

A key phrase within this seems to be the statement that other parameters must be kept constant. Is this ever the reality, and what is constant? Later in the document in the answer pertaining to DSp, there is effective recognition that some form of interrelationship will generally exist. What is perhaps more important is establishing the criticality of this relationship not that one simply exists. Later within the answer it is also stated that where an interaction exists between different parameters, the parameters should be included in a Design Space. One might be forgiven for believing that this may penalize the more diligent applicant who seeks to properly study possible interactions. Missing at present is clarity around what happens if you explore multiple parameters and find no interactions or more likely no “significant” interactions. In such circumstances where the interactions have no impact, it should be possible to justify multiple ranges (or at least a range wider than the NOR).

There is also a need to understand more about when an interaction is significant. If there are no interactions across the ranges proposed and no impact on drug substance quality is demonstrated with multivariate experiments, then surely we do not need a design space—it adds no value and makes no sense.

ref 1

ICH Q8 Pharmaceutical Development http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf.

2 Questions and answers: Improving the understanding of NORs, PARs, DSp and normal variability of process parameters, EMA/CHMP/CVMP/QWP/354895/2017.

///////////////Normal Operating Range, NOR, Proven Acceptable Range, PAR, ich, maa

FDA reaches agreement with automatic external defibrillator manufacturer over quality control issues

FDA reaches agreement with automatic external defibrillator manufacturer over quality control issues

Company must cease manufacturing until corrective action is taken

U. S. District Judge Denise J. Casper entered a consent decree of permanent injunction yesterday between the U.S. and Philips North America LLC (doing business as Philips Medical Systems and Philips Healthcare) of Andover, Massachusetts, and two of the company’s officers, Carla Kriwet, business group leader for the Patient Care and Monitoring Solutions (PCMS) business group, and Ojas Buch, vice president, head of quality and regulatory for PCMS. The PCMS business group includes the Emergency Care and Resuscitation (ECR) business unit, which markets automatic external defibrillators (AEDs) and Q-CPR Meters. Continue reading.

///////

 

“DRUG REG AFFAIRS INT” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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

Article (PDF Available) in European 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

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.

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/

Tim Sandle

The University of Manchester , Manchester

Microbiology, Biotechnology

PhD

Vijayakumar Rajendran

Majmaah University , Riyadh

Immunology, Biotechnology, Mycology

Ph.D

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

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.

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.

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.

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.

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.

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.

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.

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.

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

/////////////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?

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)

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

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

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

/////

USP revises Chapter on Pharmaceutical Water

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

New FDA Requirements for the Development of Herbal Medicinal Products

The previous FDA guideline for herbal medicinal products from 2004 is supposed to be replaced by a new version. In August 2015, the FDA has presented the draft of the revised guideline. Find out more about the FDA Guideline Botanical Drug Development.

http://www.gmp-compliance.org/enews_05045_New-FDA-Requirements-for-the-Development-of-Herbal-Medicinal-Products_9397,Z-RAM_n.html

In August 2015, the FDA has published a draft of the guideline “Botanical Drug Development”. This guideline addresses issues arising from the particular nature of herbal medicinal products. After its finalization it is supposed to replace the previous guideline from June 2004.

The general approach in the development of herbal medicinal products remained unchanged since 2004. But due to the better understanding of herbal medicinal products and the experience gained during the review of the approval documents for herbals (NDAs/New Drug Applications and INDs/Investigational New Drug Applications), specific recommendations could be adjusted. Still, new sections will be supplemented to better address the late development phase.

The draft guideline also covers the following topics:

• General, regulatory requirements
• INDs for phase 1-3 clinical trials
• NDAs for herbal medicinal products

For further information please see the full FDA document ‘Botanical Drug Development’.

Raw Material Variation into QbD Risk Assessment

Areas of discussion included how expectations for raw material control are evolving within changing regulatory and business paradigms including quality by design (QbD), counterfeiting, complex supply chains, and sourcing changes. discussed risk assessment and mitigation strategies along with supplier risk management plans.

Regulatory Considerations

the lack of a consistent definition of raw materials in regulations pertaining to the pharmaceutical industry. In its Q7 guideline, the International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) defines raw materials as “starting materials, reagents, and solvents intended for use in the production of intermediates or APIs.” However, the term as defined by different speakers could cover a wide range of materials including the following:

• starting or source materials (cell lines, viral or bacterial stocks, media components, chemicals, tissues, serum, water)

• in-process materials (resins, buffers, filters, column housings, tubing, reagents)

• excipients

• packaging components, both primary and secondary (syringes, vials, stoppers, plungers, crimps, boxes, trays, and labels)

• device/delivery components (pen/ injector components, IV bags, filters). Some regulations directly consider the control of raw materials, but they are not comprehensive and are scattered among the US Code of Federal Regulations (CFR), ICH, and other regulations/guidances. Although the regulations are not extensive, the need to control raw materials was clear from all presenters and is implicit in the sources cited below:

• 21 CFR 610.15 regarding constituents

• 21 CFR 211.80 regarding components and containers/closures

• 21 CFR 211.110 regarding control of in-process materials • ICH Q5A/D for cell substrates and viral safety

• ICH Q7 discussing the need to control materials with appropriate specifications

• ICH Q10 stating that a biomanufacturer is responsible for the quality of purchased materials

• the US bill “Country-of-Origin Labeling for Pharmaceutical Ingredients,” proposed in September 2008

• QbD principles requiring an understanding of the criticality of quality attributes for raw materials and their effect on processes and products.

Developing Control

Strategies Control of raw materials is essential to maintaining safety. Thorough knowledge of raw materials can mitigate the potential for contamination derived from such sources as microbes, chemicals, prions, and pyrogens. Raw material control for safety also includes identification — being able to verify that you have received the correct material — because the presence of an incorrectly identified material in a manufacturing process could compromise safety.

Control of raw materials is essential to ensure lot-to-lot consistency because variation in them can directly affect the variation of both product and process. So manufacturers must understand the critical material attributes (CMAs) of their raw materials and which of those affect variability — as well as how to control that variability.

You must show that you are using appropriate analytical methods to characterize raw materials. Raw materials such as polyethylene glycol (PEG) isomers, trace materials in media and water, container and closure materials, and chromatography resins all have the potential to affect lot-to-lot consistency. An effective raw material control program will also ensure consistent supplies.

A single source for a vital raw material can be a significant financial and quality-assurance risk. If a supplier goes out of business or experiences quality problems, can that raw material be obtained elsewhere? Has a second source been qualified in case the primary source is no longer available? Does the second source have the capacity to meet your needs? A QbD approach to raw material control requires that you understand the impact on your product’s critical quality attributes.

You will need to show that you understand the effect of raw material variability on your product as well as on your manufacturing process. Use of multiple lots during development can provide data on raw material lot-to-lot variability and its related effects on process and product. When that is not feasible, a manufacturer may consider including different lots of raw materials during bench-scale studies. In addition to the raw materials themselves, you should gain an understanding of whether and how raw material degradants might affect your process or product.

A QbD approach can use relevant knowledge to help you define how to go about setting specifications, in-process controls (IPCs), and handling conditions. Testing of Raw Materials The forum discussed what levels of testing are important for specific raw materials. A supplier’s certificate of analysis (CoA) is never sufficient for raw materials because good manufacturing practices (GMPs) require appropriate testing, and at a minimum, testing for identity. The material ordered may include additives, preservatives, degradation products, or contaminants. You must verify that the CoA is appropriate for control of the raw material, but you can’t assume that at the outset.

Similarly, CoA verification may be necessary only once a year once your experience with a given supplier has shown that quality is consistent. Vendor qualification is an important factor in defining your testing needs. To ensure the quality of raw materials against adulteration, identity testing is essential. Currently, tests with fingerprint techniques — e.g., nuclear magnetic resonance (NMR) imaging and Raman, nearinfrared (NIR), and Fourier-transform infrared (FTIR) spectroscopy — are used to assure the identity and quality of raw materials.

Whatever techniques you use, it is important to retain samples for future investigations. Photographic libraries of materials and their packaging have also proven useful for identifying and preventing use of counterfeit products. How often and in how much depth you need to verify a CoA through independent testing is an important consideration, especially for environments in which counterfeiting or contamination can occur.

Once you understand the CMAs of your raw materials, you need to identify which tests are relevant for testing specific quality attributes (QAs) of those raw materials. Sampling plans need careful consideration and should be risk based, dependent on the nature and use of the RM, and any regulatory requirements. Such plans should always be justified in a report available for inspection and/or filing.

It is important to consider RM stability and whether any special tests for degradants are needed for release of the material over time. A stability profile will dictate the purchasing program (storage of large quantities or buying as needed) as well as affect the associated testing strategy.

Supply Quality Management:

Ensuring Quality and Availability It is becoming increasingly evident in the current supply chain environment that management of suppliers and the “cold chain” is essential to assuring the quality of raw materials. How often and how thoroughly you perform vendor audits depends on your experience with a given vendor.

A manufacturer’s general experience with a vendor (prior knowledge) is an important criterion used to evaluate that vendor’s suitability to supply raw materials. Items to consider when selecting a vendor include its quality systems and its solvency, as well as its length of time in business, its geographic area, and whether it supplies multiple industries or just one or two drug manufacturers. Those form part of a risk assessment relating to suppliers to be described in more detail below.

Ensuring both the availability and qualification of secondary suppliers is important as well. Practices such as split purchasing may help ensure that you have good working relationships with multiple vendors. Strict change control sections should be included in supplier agreements and should include details requiring a vendor to notify you of changes in its product or suppliers. Such agreements should also provide for impact assessments from both supplier and manufacturer in the event that a supplier makes any changes. Supply chain traceability is not as straightforward as it might seem.

Although most manufacturers use country-of-origin (COO) questionnaires, those often prove less than ideal in revealing what you need to know. It is critical to craft questions that get the in-depth answers you need. For example, rather than asking “Do you purchase supplies from any high-risk countries?” you might ask “From what countries do you purchase supplies?” If the specified countries include any you consider to be high risk, you can follow up or choose another supplier.

It is critical to use risk-assessment techniques for determining traceability to avoid a false sense of security that can lead to costly or even deadly errors. It is sometimes unclear exactly what roles are played by whom in a supply chain.

Which companies are manufacturers, which are distributors, and which are intermediaries is not necessarily clear. A company that simply repackages a raw material from 55-gallon drums into smaller containers may consider itself a manufacturer. Due diligence will help ensure that you really know where your raw materials originated. As part of assessing supply chain complexity, forum participants were informed of a proposed program whereby industry creates a system of cooperative audits in which vendors would be audited by a selected team representing all industry rather than multiple auditors from each company continuously auditing suppliers.

The resulting audits would lead to certification that would assure all purchasers that each vendor meets certain defined criteria. Such a “360° Rx” program would enable increased depth of supplier audits and save manufacturers time and money (see box, right). The Role of Compendial Standards: Compendia provide some assurance of minimum quality standards for specified materials. However, compendial standards may differ among the pharmacopoeias.

Few of the complex raw materials (e.g., culture media, soy, yeastolates, most growth factors) used in biotechnology manufacturing are compendial, and those that are (e.g., insulin) may not have the appropriate compendial limits on specific quality attributes — or even test for quality attributes necessary to control pharmaceutical manufacturing. Even for standard chemical raw materials (e.g., trace metals), compendial standards may not focus on quality attributes relevant for biotechnology process and product quality assurance.

Those may be product- and/or process-specific. Furthermore, compendial standards do not necessarily help control for contamination, counterfeiting, or supply chain issues because a supplier can simply state it meets compendia — a statement that currently requires no certification

Risk Management

Risk assessments are an important tool for ensuring the safety, efficacy, consistency, and supply of pharmaceutical products. Many companies in both the United States and the European Union are using ICH Q9 as a basis for risk assessment, control, communication, and future review.

Risk assessments should begin by identifying all raw materials and assessing their criticality to product safety, efficacy, and supply. RM risk assessments require cross-functional input from all departments including supply, product development, manufacturing, quality control, quality assurance, clinical, and any other contributors. It was clear from this forum’s discussions that risk assessments are only as good as the people who carry them out. Having the right expertise over a spectrum of areas is vital if any risk assessment is to be meaningful. Multiple risk assessment tools exist, but in general, a good risk assessment must address concepts such as impact/ severity and likelihood/detectability.

One tool discussed at the forum (Figure 1) used nine blocks to score a supplier’s performance against material risk levels for audits, supplier qualification, supplier monitoring, change control, material specifications and testing, quality agreements, supplier certification, and sourcing, or other appropriate combinations of factors. Risk assessment should also be performed in relation to country of origin. It is critical to be able to trace your raw materials to their source. Just as a biopharmaceutical manufacturer audits its suppliers, those suppliers must also know, audit, and qualify their own distributors.

It is now well known that there are high-risk geographic areas where additional caution should be exercised to assure purity and identity of sourced materials. A potentially overlooked risk assessment issue is that manufacturers need to evaluate their raw materials and products in relation to opportunities for someone to make a profit through adulteration (e.g., by diluting a product to increase volume, and thus sales income). Any materials identified in such an evaluation should be managed with particular caution.

Risk assessments ensure that appropriate control strategies and raw materials (e.g., grade, origin) have been selected, which is relevant to a QbD approach. For regulatory filings, acceptable specifications, raw materials, and control strategies are tested with the necessary acceptance criteriia to ensure the performance of a process and the quality of its ultimate products. A periodic risk review should include more than a mere cursory review of individual risk assessments. It should reevaluate the risk program itself based on experience and lessons learned. Your risk assessment should be phase-appropriate, and as such it will change as data become available throughout development.

Early on, your raw materials risk assessment can be based on platform and previous knowledge, on the quality assurance of your suppliers, and adventitious agent introduction. As a manufacturing process develops, you will need to reevaluate that risk assessment including commercial considerations of scale and production frequency, highrisk raw materials control strategy, and handling and storage requirements.

During commercialization, design of experiments (DoEs) and collated knowledge will further define the CQAs of both product and RMs as well as potential and actual interactions among RMs, process, and product. At that point, you will be able to define and justify the raw materials for your commercial process and refine their specifications.

By the time your product is ready for market launch, you will have updated the failure modes and effects analysis (FMEA), completed your raw materials specifications, set your sourcing strategy, put in place your supplier qualification program, defined your raw material control strategy, and made your risk assessment ready for filing. The morning’s session resulted in a list of elements to be included in a raw materials risk assessment

 

Elements of Raw Material

Risk Assessments Is the raw material biological, chemical, or physical (such as tubing or stoppers, materials that are not actual components of the end product)? How likely is the raw material to introduce biological or chemical contamination?

Is the raw material or are its degradants able to directly affect the safety and/or efficacy of a drug substance (e.g., toxicity, chemical modifications)?

How complex is the raw material itself or its impurity profile? How much prior knowledge (e.g., historical or published knowledge, current experience) do you have regarding the raw material? What is the Intended use of the raw material (e.g., as a buffer, reagent, or excipient)?

Where in the manufacturing process will this raw material will be used (upstream/ downstream)?

What is the extent of supply chain traceability (considering country of origin, supply chain complexity, and supply chain security)?

What is the extent of supplier quality assurance (from audits, monitoring, historical experience)?

How extensive is the characterization of the raw material (how well can the raw material be characterized; standard existing methods or novel techniques; the RM’s impact on test methods)?

How stable is the raw material? Is the raw material new to the process or a result of a change to an existing raw material (if a change, what studies have been executed to assure comparability)?

What is the depth of knowledge of the RM’s own manufacturing process to assess the risk associated with its use (e.g., process contaminants)?

Does the use of the raw material in a manufacturing environment present safety and/or handling risks? Does your process have the ability to clear the raw material?

Are there associated business risks (e.g., a solesource or multiple-source material, unique or not to the pharmaceutical industry, custom-made or not, and the supplier’s ability to consistently meet specific requirements)?

What is your level of understanding of the raw material CMAs?

Benefits of Implementing QbD

Benefits for the FDAEnhances scientific foundation for review Provides for better coordination across review, compliance, and inspection Improves information in regulatory submissions Provides for better consistency Improves quality of review (establishing a quality management system for CMC) Provides for more flexibility in decision making Ensures decisions made on scientific and not on empirical information Involves various disciplines in decision making Uses resources to address higher risks

Benefits for Industry Ensures better design of products with fewer problems in manufacturing Reduces number of manufacturing supplements required for postmarket changes; relies on process and risk understanding and risk mitigation Allows for implementation of new technology to improve manufacturing without regulatory scrutiny Allows for possible reduction in overall costs of manufacturing; creates less waste Ensures less hassle during review, reduces deficiencies, speeds approvals Improves interaction with the FDA; operates on a scientific rather than on a process level Allows for continuous improvements in products and manufacturing processes Allows for better understanding of how APIs and excipients affect manufacturing Relates manufacturing to clinical during design Provides a better overall business model

Frequently Used QbD Terms 

 

Quality Attribute: A physical, chemical, or microbiological property or characteristic of a material that directly or indirectly alters quality	Critical Quality Attribute (CQA): A quality attribute that must be controlled within predefined limits to ensure that a product meets its intended safety, efficacy, stability, and performance
Real-Time Release (RTR): Ability to evaluate and ensure acceptable quality of an in-process and/or final product based on process data, including valid combination of assessment of material attributes by direct and/or indirect process measurements and assessment of critical process parameters and their effects on in-process material attributes	Process Parameter: An input variable or condition of a manufacturing process that can be directly controlled in the process. Typically, such parameters are physical or chemical (e.g., temperature, process time, column flow rate, column volume, reagent concentration, or buffer pH).
Critical Process Parameter (CPP): A process parameter whose variability has an influence on a CQA and therefore should be monitored or controlled to ensure a process produces a desired quality.	Process Performance Attribute: An output variable or outcome that cannot be directly controlled but is an indicator that a process performed as expected
Key Process Parameter (KPP): An input process parameter that should be carefully controlled within a narrow range and is essential for process performance; a key process parameter does not affect product quality attributes. If the acceptable range is exceeded, it may affect the process (e.g., yield, duration) but not product quality.	Non-Key Process Parameter: An input parameter that has been demonstrated to be easily controlled or has a wide acceptable limit. Such parameters may influence quality or process performance if acceptable limits are exceeded.
Design Space: The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality; working within a design space is not considered to be a change requiring regulatory approval. Movement out of a design space is considered to be a change and would normally initiate a regulatory postapproval change process. Design space is proposed by an applicant and is subject to regulatory assessment and approval (ICH Q8).	Control Strategy: A planned set of controls, derived from current product and process understanding, that ensures process performance and product quality; such controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished-product specifications, and associated methods, and frequency of monitoring and control (ICH Q10).
Quality Target Product Profile (QTPP): A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure desired quality, taking into account safety and efficacy of a drug product