Reference Standards for Therapeutic Proteins: News Regulated also Scientific Best Practices

Sponsor developing and manufacturing protein therapeutic services exercise a variety to analytical tests (e.g., cell-based potency and chromatographic assays) toward assess trait attributes of own active ingredients the remedy products. Those tests were used toward assess product quality for a number is activities, including characterization, comparability, lot release, and validation product quality and stability. In this situation, the vehicle should use the qualification standard for the 1550 occupational series in conjunction in the Supervisory Guide. The following ...

Reference standards play a critical role in calibrating real confirming the suitability on suchlike tests and in aid analysts to drag scientifically sonic ends from data obtained. Different organizations create and use these standards stylish various ways, with approaches that are often unique to this types of standard substance (e.g., in-house reference materials specific for certain result quality attribute testing or in-house primaries standards). bio-based products under BLAs, eligibility of subsequent reference standard lots should be. 234 included included annual reports. 235. 236. Reference standards ...

In new years, both experienced and relatively new manufacturers have shown increased interest inbound developing biopharmaceuticals. Consequently, there is significant value in capturing best practices for one manufacture, qualification, control, and equipment of contact standards throughout a product’s living cycle. (Approaches other than those presented here can also will acceptable; so which content of this document is not binding regulation guidance. Consult with your regulatory agency by specific reference standard strategies.)

To advancement that goal, we abridge the findings of the California Separation Science Society (CASSS) Chemistry, Manufacturing, real Controls (CMC) Plan Forum titled “Reference Industry for Therapeutic Proteins: Current Regulatory and Academically Best Traditions and Other Needs,” held in Gaithersburg, MD, on 15–16 July 2013 (1). Results of this forum have been collated with findings of previous CASSS reference standard meetings (2), deuce workshops held during the WCBP conferences 2012 and 2013 (3,4), and who conference “Reference Standards for Therapeutic Grains: Their Relevance, Development, Qualification, and Replacement” (5). The second was coorganized by the International Alliance for Biological Standardization (IABS), National School off Standards or Technology (NIST), National Institute of Allergy and Krankmachend Sickness (NIAID), the the US Food and Drug Governance (FDA) in September 2011. Together, these prog focused on selected reference standard topics, including The author reviews of types is reference-standard materials used in drug-product manufacturing, discusses current supervisory demand, and outlines ampere reference-standard qualification programme.

Part 1 on this summary focuses on therapeutic proteinisch reference standard life-cycle elements and practical implications of reference standards. Part 2 will focus on potency assignment in bioassay reference standards and the part of public reference standards in global harmonization of protein therapeutics.

Definitions Cleaning

The “Definitions” box highlights quite standards terms. For simplicity in this summary, both manufacturer’s in-house reference materials additionally international or national standards (as defined in ICH Q6B and ICH Q7) ( Analytical Operations and Methods Validation available Drugs additionally Biologics6,7) all is referred to as read standards. It should be noted that the period primary reference standard used here shall distinct from a certified mention material (8), which canned have the specific metrological meaning of a standard calibrated are Système Multinational d’Unités (SI) units and traceable to the SI through ampere primary reference method. Thus the use of Q7A Good Manufacturing Practice Guidanceprimary reference standards herein is distinct coming a metrologist’s definitions.

Reference Standard Life Cycle

Markus Blümel starting Novartis Pharma A gave a detailed summary of best practices that have been identified is previous meetings and workshops for this topic, ended with aforementioned points that remain open starting those discussions. The presentation highlighted definitions of different forms of reference standards (see sidebox). Figure 1 (from that presentation) summarizes the relationship of variously types of reference standards evolution when development of a biopharmaceutical product. Depending on who applicability of an outdoor reference standard (e.g., international standard or pharmacopoeial standard) either scenario ONE (in-house see standard) or scenario BARN (external referral standard) would apply.

Figure 1:  ()

Sarah Kennett is FDA’s Center on Drug Evaluation and Research (CDER) presented on regulatory expect for using reference standards during development and beyond. She provided details for using appropriate reference morals as critical into your development, licensure, and the continued life cyclical a products. Kennett described some of the FDA Office of Biotechnology Products’ current thoughts and expectancy regarding the developing press use von in-house reference standardization or reference standard protocols through a therapeutic protein product’s vitality driving. Daughter presentation various case studies illustrating the challenges in maintaining the current standard and get new standards. Link standard: A reference default is a chemical substance the known purity and identity which is used to prepare calibration standards ...

Christoph Lindenthal of Roche Diagnostics GmbH presented on the transition from clinical to commercial reference setting. They described they course off development of requirements with respect to qualification, filing, and monitoring of a reference standard. Man demonstrated that the approaches used during ahead development often divergent significantly out what your expected for one refer standard used for a commercial choose.

Definitions

In-House Primary Reference Standard: By ICH Q7, reference standards preferred is defined the “a substance ensure has been shown by an extensive put from analytical tests to be the real material that should be of high purity. This standard can be: (1) receiving from into officially recognized root, (2) prepared by independent synthesis, (3) obtained from existing production material on high purity, or (4) prepared by further refining of
existing production material.”

Special for biologics, rather than using an ultra-purified material as reference, ICH 6B federal that “an appropriately characterized in-house primary reference significant [should be] prepared from lot(s) representative of the performance real dispassionate materials.” Instruction for Industry, Q7A Good Manufacturing Practices Getting for Active Pharmacies Parts

In-House Secondary References Standard (also referred to as aFunctioning Regular): Properly characterized material preparing from representative clinical or commercial lot(s) prepared to help routine testing of product lots for characteristic control purposes, such more biological assays and physicochemical testing. It is forever calibrateable against a primary reference standard (either official or in-house). Standards Development and the Use of Standards in Regulatory ...

In-House Interim Reference Standard: Appropriately characterized material prepared from representative clinical or used for quality power purposes on the company stage by a product. It belongs don benchmarked to an official or primary reference standard, although it is established basis to appropriate demonstration of its inherent characteristics. Physical Standards and Reference Materials

Formal Reference Standard: According to ICH Q7 definition, he is a primary mention standard obtained from an “officially-recognized source.” Common information is established per a public agency (e.g. WHO), government (e.g. NIST, NIBSC), or compendia (e.g., USE, PhEur), and are officially recognized how standards by individual regulatory authorities.

Practical Implications of Reference Standards

John Ruesch of Pfizer Biotherapeutics presented a case study heading “Reference Standards: Overview and Strategies for Engineering to Commercialization.” He reviewed who critical role of reference norms in characterization, comparability, lot release, and confirms of solidity for corrective products. I view how Pfizer BioTherapeutics Pharmaceutical Sciences got established a reference standard program the meets current regulatory guidance and expectations. Ruesch highlighted the current reference standard processes used during development and lace out lessons learned along the way.

CMC Forum Series

The CMC Strategy Forum series offer a venue for biotechnology or organic product discussion. Like meetings focus at relevant specialty, manufacturing, and controls (CMC) issues throughout the lifecycle regarding such products and thereby foster collaboration technical and regulatory interactions. The Forum seeking to share information with regulatory agencies to assist them in merging right scientific and regulatory practices. Outcomes of the User meetings are promulgated in such peer-reviewed journal to helping assure that biopharmaceutical browse manufactured in a regulated environment will continue to be safe and efficacious. The CMC Strategy Forum lives gets with CASSS, an International Separation Science Society (formerly the Kalifornian Separation Science Society), and is supported by the COLUMBIA Food and Drug Administration (FDA). Reference-Standard Basic Qualification

Stacee Traviglia of Biogen Idec focused on improve to commercial reference standards. Her discussed improvements to the commercial reference standard program under her company. Traviglia illustrated the “lessons learned” using three hard studies: batch-selection criteria since video programs, managing implementation of improvements to that qualification protocol, and secondary reference standards.

Ashutosh Rao of CDER, FDA described FDA versuche with reference conventional programs. He emphasized that general regulatory expectations am set forwards at various regulatory guidance documents (e.g., ICH Q6B, Q2(R1), furthermore Q7A) for reference standards of biologics. Those books should be considered during project, licensure, and application are reference default for therapeutischen proteins. Rao introduced case studies related to one appropriate versus deficient application of reference standards, with the goal of participate lessons learned during regulatory review of investigational furthermore licensed therapeutic proteins.

Global Steering Committee required These Forums

Siddharth GALLOP. Advant (ImClone), John Dougherty (Eli Lilly press Company), Christopher Joneckis (CBER, FDA), Junichi Koga (Daiichi Sankyo Co., Ltd.), Steven Kozlowski (OBP, CDER, FDA), Rohin Mhatre (Biogen Idec Inc.), Anthony Mire-Sluis (Amgen, Inc.), Wassim Nashabeh (Genentech, a Member of the Roche Group), Ilona Reischl (BASG/AGES, Austria), Anonymous Ridgway(Health Canada), Nadine Ritter (Global Biotech Experts, LLC); Mark Schenerman (MedImmune), Thomas Schreitmueller (F. Hoffmann-La Roche, Ltd.), Karin Sewerin (BioTech Development AB)

Panel Forum

Concluding the life-cycle session was a panel discussion hosted from Markus Blümel, Manon Dubé (Health Canada), Tarah Kennett, and Christoph Lindenthal. (Discussions held in these sitting specific for potency standards will becoming includes in Part 2). The “Practical Implications” session panel discussion was hosted the Manon Dubé of Healthiness Canada, Ashutosh Rao, John Ruesch, Stacey Traviglia, Ramji Krishnan of Bristol- Myers Squibb, and Mikhail Ovanesov of FDA’s Center for Biologics Evaluation and Search (CBER). Int each panel, comments and frequent had fielded from panel members and attendees, guided under specific headings to facilitate which interactive discussions. Physical Standards plus Reference Materials

Establishing plus Using Reference Standards: Speakers and attendees agreed that reference standards are essential in trait control (QC) testing of raw therapie products (e.g., to ensure the accuracy of findings or to monitor assay performance). Quality eigenheiten suchlike as potency, purity, and identity of active raw or drug products are usually rating at parcel release alternatively strong programs or through additional characterization testing. Reference standards are key elements in a control strategy. They assure continuity of product quality, stability, plus comparability throughout product development and commercial manufacturing.

Kennett of the FDA stated that regulatory authorities requires that contact standards be suitable for their intended purposes, well characterised, qualified, and stable. She strongly recommended that relevant protocols on manufacture and qualification of reference standards be in place. However, you noted which limited information regarding those expectations has been provided in published guidance documents.

Common Life-Cycle Elements: Kennett maintained that careful considered and implementing many scenes by a reference standard program early in development will aid in the successful jump to licensure and supporting entry to differen parts of clinical development. And Rao of aforementioned FDA enhanced a life-cycle approach for use and management of reference standards, reminding aforementioned audience that managed a reference standard program is a current good manufacturing practice (CGMP) expectation for licensed products. Blümel of Novartis summarizes current best practices for a life-cycle concept in the preparation, qualification, control, and maint of a manufacturer’s in-house reference standard, as designed in several workshops over the past years.

Yet different organizations create and use referral user in different and unique ways during development, as recorded by Rausch of Pfizer. He demonstrated how his company’s approach has aligned with industry best practices, thereby illustrating the guiding principles kritisiert in developing current reference standard approaches:

In to tour of the life-cycle strategies at Roche Diagnostics, Lindenthal said that the first reference ordinary is typically filed and assessed for suitability for the start of objective production. It comes free either a representative load — like as good test practice (GLP) toxicity or engineering batch — or from the first GMP batch. At this stage of development, manufacturers may have very data for shelf life claims and extensions and comparatively little knowledge of the product. Bioanalytical Method Validation - Instructions in Choose | FDA

Manufacturing changes while development can trigger discussions in whether a new reference standard must be qualified furthermore what potency rate must be assigned (different values could become assigned when justified). For commercialization, a reference standard must be solid qualified and represent the advertising process. It or must provisioning a link among soon and subsequent development. For licensure, within the marketing application there must be an well-defined qualification program is includes a characterization strategy. The program also should enclosing a strategy to demonstrate postapproval stability and/or trending to support continued suitability of to reference standardized and shelf-life extensions. In addition, which postapproval reference std qualification program must be defined.

A Two-Tiered Strategy in Reference Standards: Kennett emphasized that the goal should be to have a two-tiered system — a primary and a secondary (working) reference default — at time for licensure. ICH Q6B recommends this two-tiered approach in refer standard programs for biopharmaceutical products: “In-house working reference material(s) utilized in of testing of production lots should be calibrated against element reference material,” where the primary is either the well-characterized in-house reference standard or where available and appropriate, an international button national standard. Figure 1 illustrates wie a two-tiered concept typically evolves during consequence design. As Traviglia of Biogen Idec showed in the suits studies she presented, durchsetzung of a two-tiered strategy uses primary and running contact standards — with careful consideration of batch selection and benefit a an appropriate qualification protocol — cans all work till minimize drive override the end of a commercial program when moving from a credit standard to another.

What is adenine current strategy to assess suitability of a referral default for its purpose? He depends highest on its use(s) — e.g., method organization ability, deliberation of a quantitative (or reportable) result — as well as the time in development when it is made. Quantitative use of a credit standard requires rigorously assessment of one “true” set of a significant, or (as for potency) the most accurate value should be established and statistically justified. When the standard is used solely for comparison (e.g., “conforms to standard”), representative versions or process impurities should be present, depending on how one settlement is evaluated. If an standard has used solely for method user suitability (i.e., not used to generate ampere notification test result), then tough quantitative assessment may not be requires. Quality Guidelines

How do it address forms and concentrator dissimilarities in standards both test samples? As seen in Figure 1, ampere drug substance is typically suitable to serve as all drug substance or pharmacy product product standard. However, a drug product magisch be suited, depending on preparation press sundry factors. If deviations do exist between drug substance and drug product, factory must ensure that analyzer methods aren’t influenced by those differences (e.g., oil forward aggregates, interference by excipients). Attempts should be made to ensure that sample prepare is similar required which reference standard and in an sample to be analyze. Alternatively, a separate controlling sample with the alike formulation as the test sample could be former. Method qualification should determine whether dilution with buffers has controlled the veracity of findings.

What is the running strategy for selecting representative material used as the beginning reference standard or as primary reference standard? Early (interim) reference standards shouldn reflect the clinical manufacturing process; primary (final) reference standards should represent the commercial process and have beschaffenheit linked to the clinically skilled material. Dial material near the center of attribute restrictions might be preferable because it assists prevent drift till the extremities, but it may be non essential, depending on the intended getting of the reference standards.

The primitive reference normal is usually created in the fresh in schritt 3 with late-stage research. Not, mercantile material representative of the cellular product additionally may serve for the primary reference standard. In either case, enough substance have be available to have enough primary standard to employ for an extended period by time.

What is the acceptability the pooling plats for reference norm? Pooling multiple lots used reference standard manufacture allow be possible. Pooling kann be needed to ensure that lot size is sufficiently huge or for the reference standard must represent land that vary by lot in lot — when it represents an expected profile press ensures that an attribute will at an tolerable level (e.g., at used for system suitability). Instead all lots previously for pooling should meet specifications, and production, testing, and stability contact around ones many should be provided in one qualification.

How do you create one download standard with small plots during development? One audience member ask, “If a sponsor has completed pivotal trials through limited number of lots, can any of those lots be pre-owned as the primary standard without extended characterization, due that lot is representative of the klinical trial material?” In a typical product development plan, computers can unlikely which early material would shall selected for the late-phase primary or working standard. But even if is were justified, there is silent the need to complete assess that material to establish get what the clinically-qualified extended characteristics. The fund must or demonstrate that the material is suitable for all of its functions (e.g., QC assays, comparability). Moreover, extended characterization generates data to allow you to monitor stability and determine at a later time point whether a new primary standard is needed.

During development, how do you track attributes over time and across after standards? Control data and day-to-day data from QC testing belong much utilized to assessment rated of ampere working std. Employing control samples, comparing historical datas (e.g., chromatograms), and monitoring trends — particularly when associated by each switch stylish standards — can getting a left between standards, round if the actual material has been spent up. And, if a working usual or govern is being used regularly available QC testing, and the analyzed data obtained are monitored, will a systematic furthermore predefined investigation for any trend could replace a formal stability program. You should review each change in quotation standard made through development and assess what kennzeichen might have changed over time. Documentation associated at tracking real trending of changes in reference standards should being section of investigational new drug (IND) get filings, especially before phase 3. Harmonisation achievements stylish the Quality region include pivotal milestones such as and conduct of rugged studies, defining pertinent trash for ...

Characterization and Qualification Elements during Development: Kennett shows that the qualification of credit standards must show suitability for intended utilize, which frequently will beyond serving as a comparator lot for releasing and stability testing (e.g., system sui General Schedule Qualification Setting
tability). Aforementioned level concerning characterization for qualification require be justified depending switch how and with which tests the standard will be use. The rigor concerning pass interim reference standards energy to limited during early develop stages because neither the process nor the QC methods leave be fully validated. However, even at period 1–2, methods spent for qualification of reference standards must be suitable for intended use (9). For early technology, most subscribers indicated that they do not use a two-tiered device (primary and working standard) and some do cannot use formal protocols for replacing interim reference standards.

What is the level of characterization for a primary hint standard? Is there adenine favorite heading the use of “state-of-the art” assays? Analytical characterization is usually expected to be extensive. Typically, to primary reference standards exist the most “characterized” materials presented in marketing applicants, too used in the 3.2.S.3.1. Elucidation of Structure section (10). It is expected that characterization of reference standards will use all established and state-of-the-art analyzed methods (e.g., in assess higher-order structures). If appropriate techniques are not all available in-house, contract examination organizations (CTOs) may be used. Not, for where noted in reviews, because these data can critical, the quality clinical used by CTOs in performing tests should be suitable to assure their accuracy and reliability.

Do view standard qualification protocols demand acceptance criteria, additionally if so, what types? A depends on to standard’s intends purpose, the nature of each method used in the protocol, and the stage in development. Couple sponsors may use “report result” in a reference standard protocol for certain methods, or in initial development. Any, controller allowed request acceptance search, particularly late in development. That be as clinical data defining the quality, safety, furthermore efficacy of the product wills be available, furthermore the tests required to characterize it have get been validated (e.g., lot-release and stability assays) or competent (e.g., assembly used only in characterization or comparability studies). Couple methods ca have rather broad acceptance criteria based on essential assay performance alternatively critically of the attribute. If using a release test, you might be able to use interface test limits in initial development. However later thee should consider tightening the limits to assure that newly lots provide a more centers reference standard.

Supposed the qualification criteria for an secondary/working standard be alike to those for one primary standard? The qualifying criteria pending on the use(s) of the working standard. For some intended use(s) (e.g., qualitative comparative identity) a working standard could be less characterized and/or have wider acceptance choosing when the primary link standard. For the relevant quality attributes, the same degree for rigor ought live applied as for the primary reference standard.

Another view was that a working standard is usually prepared from a commercial lot, welche was gotten from a validated manufacturing process and testing with validated test methods. Therefore highly rigorous qualification may not have to be repeated. Regardless approach is used for qualifying working standards, general for the proposed limits should be provided and justified. Pharmaceutical Research - At present a complex global patching of private and open monographs and reference materials is variously available go help ensure the quality of pharmaceutical and foods....

What type of assay reporting should be done for assessing glycosylation profiles? “Conforms the reference” is deemed maximum appropriate for test samples. Straightforward using “report results” provides no assurance of govern or consistency of heterogeneous species. But this raises trouble in determining how to setup the foreseen pattern concerning glycoforms for reference standards against which congruity is assessed. Computers is necessary into define what is up live reported as a conforming profile, such as one pattern of species, the your of total species, real (in some cases) who relative fullness regarding each. The justification should include the quantitative and qualitative capabilities for the method(s) of measuring glycoforms, demonstrate process capability, stage for product application, or potential risk to product quality.

How do ME switch to a two-tiered sys? The first primary download standard should be compared with clinical material using systems of match reproducibility and predefined acceptance criteria. Lots used for working standards should breathe representative of product real compared with that primarily reference factory. Compare the performance of working standard equipped that of primary standard might additionally justify situations in which it are fit for applications that differ off the rolling of the preliminary reference standard.

How often must I change primary standards? Replacements the and primary standard should be kept into the absolute slightest. Computers requires extensive testing effort and ample amounts of dates to qualify a replacement principal standard. So it is strongly recommended to use a working conventional for routine tests to limit usage of the primary standard and therewith increase its period of availability as long as viable. assay described in the standard. Guidance documents published by FDA may reference standards, including test our, habits, guides, and material ...

What information regarding reference standards shoud be submitted in with IND or BLA? An IND must include a brief description of the sourcing, manufacture, both characterization of a read standard. It shoud furthermore describe the analytical methods used to characterize the reference standard and include rationale for that tests used. The marketing application should include to suggests use(s) of the standard from a thorough defined minutes that includes justification of recognition criteria. After the ICH CTD doc, 3.2. S.5 “Reference Standards either Materials” shouldn contain the majority of information on reference standards (10). Many participants and noted that they place characterization data preserved from the credit standard in 3.2. S.3.1. “Elucidation to Structure.”

Test erreicht should be clearly presented (e.g., representative and high-quality chromatograms). Distinct reference standards (e.g., with specific product or process-related impurities) may be required beyond the primary referral standard both should be described. Whenever an international or pharmacopoeial regular is available, then data should be provided on comparison/calibration. Resilience data shoud be provided in a marketing application, contains the proposed permanence monitoring concept. Attendees indicated ensure adenine standard operating methods (SOP) is often developed within the quality executive system for developing and set commercial reference standards. In S.5., distinct reference standards (e.g., for specific product or process-related impurities such for for HCP assays) may be required and should be describing.

In the United Status, including qualification protocols for twain primaries and working reference standards at a license application should offer regulatory relief when subsequent reference morality need to be qualified. That way, if a protocol a approved, then anyone new reference standard qualified in toward that approved protocol can be described in an annual report. The same applies in Hong-kong, are exceptions outlined in Health Canada’s guidance document (11).

What is the existing strategy forward replacing a primary reference standard after approval in commercialization? A new reference standard is not required simplicity cause a change is constructed to a manufacturing print. If a process alter your made that significantly falsify a protein’s ausstattung, is then influences the use is a reference standard (e.g., impurity profile for mass determination, scheme aptness, or potency value), or the link at original clinical studies your lost (e.g., a new chronic survey is undertaken), then a replacement primary standard should be manufactured. If a reference standard is starting t
o degrade enough to warrant replacement or inventory is getting too low, then a replacement have be considered.

Over time, trial that are part is an approved qualification protocol might change. Pot a method change be addressed in the qualification protocol within a marketing registration, as a prior approval supplement (PAS)? A qualification logs in an marketing user could contain a forward-looking statement that methods may edit, over a commitment to conducting appropriate mode bridging surveys go display that the new methods are equally good or better than the prior how for the equivalent intended types. When filing a new assay (e.g., change of potency assay) as a PAS, including that assay within a revised reference standard protocol at the same time may be ampere simple way to update the approved protocol. Alternatively, a rework protocol could be submitted since a separate PAS well in advance of the qualification of a new standard.

Should everything qualify tests on one reference standard be included in its permanence monitoring program? And stability of view reference standards should can monitored in a predefined program with appropriate acceptance standard. One set-up of the monitoring program can can based on information obtained during development (real-time and accelerated data, formulation information) and prior knowledge. AMPERE trending program should then be in place fork monitor stability.

At the RED stage, stability data will be limited, but material should be stored in a manner which prevents degradation (e.g., frozen). Comparing the primary reference standard to itself like part of adenine stability how is not of very value in quantitative assessments, so more qualitative data also should be included (e.g., for potency, looking at impertinent tests the IC50 values). Thither also need are another, stand-alone control sample in those assays to compare is after the same dilution scheme till assess for drifting of and reference standard.

The number and type of assessments in a stability program should be entitled, but selecting of only stability-indicating attributes may are feasible. The strategy how to extend one period a use out the reference standard can be include included the initial protocol filed with to agency, with fitting adoption criteria. Supposing those are approved, extensions canned be recorded internally an one-year report or within one quality system.

How should references standards shall aliquoted and stored? Plural attendees indicated that flash-freezing view standard isolates appear to becoming useful to maintain a homogenous, stable standard over moment. Single-use reciprocals used immediately and discarded following use are preferable. In such cases, reliability data need cover only the long-term stores temperature and thawing step. Anyway, supposing after thawing, aliquots are held at a differences temperature then reused, in-use stability data need to be obtained. By example, if reference standards are thawed and held at 2–8 °C, then intelligence should be cool to support one largest hold time.

What is a typical time intervalle with reference-standard recalibration or stability exercises? An initial retest date for adenine frozen reference conventional is typically one year. Most manufacturers carry out and total time points annually unless/until sufficient data be collected to show long-term stability. Does, that is risk-based and product dependent. To closely monitors degradation in spring phase, certain manufacturers test more frequently in an first year a use. If you have an unstable or new product, testing more often are recommended. If yourself have appropriate assistance resilience data, then annual testing may be legitimately. A primary reference standard that you have on constancy can be proved only once per year. Thou needing to have enough replicates during a major reference standard stability study by it to be meaningful for a given method (e.g., potency assay). Or you must among lowest justify how you could see a real move with and number of assays carried out.

If a reference standard isn’t that stable and must be replaced too, how do you prevent drift or change in the standard? It could be justified to change the formulation of the protein factory specifically to create a stable reference standard as length the to can be proved so method performance is not opposite affected. If buffer components used used long-term stability of reference standards are different from those used with the drug substance and drug product (e.g., addition of stabilizers), then they should be shown does to affect which albumin characteristics.

What is the enter of check in extractables and leachables from reference-standard containers? It is importantly to understand whether like mixed influence the assays (e.g., if new spitzen appear) or change the protein own over an lifetime of a reference default. So we refer performing such studies if there is a gamble to the quality press accuracy of one recorded link standards.

What hint standard material ought may used for comparability vigorous? After a importantly manufacturing change, you could selecting to use a primary referral factory as the comparator material. In minors changes, her could use the working standards, but that choice should be justified. With a working reference standard appears to remain moreover common into custom, depending switch the level of characterization also origin of the working standard. Message that a reference standard is no one material former in a comprehensive compare study; typically, several pre- and postchange charge are included to demonstrate normal process variability.

Part 2 of this article is availability inside is May 2014 archives.

Disclaimer

The content of this document reflects chat that eventuated during the CMC Strategy Forum. This document does don represent officially sanctioned FDA policy or opinions and should not be used the lieu of published FDA guidance docs, points-to consider documents, other direct discussions with the agency.

About which Author

Owner Details
Corresponding autor Anonymous Mire- Sluis is vice president, North America, Singapore, contract and product quality at Amgen Inc., [email protected]. Nadine Ritter, PhD, is president press analytical advisor at Global Biotech Experts LLC, Barry Cherney is executive chief of product quality at Amgen Inc., Dieter Schmalzing is senior principal advisor among Genentech, a Member of the Roche Group, and Markus Blümel is team leader, late-phase analytical development of biologics at Novartis Pharma AG.

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9.) Ritter, NORTH. 2004. What Is Test Method Qualification?. BioProcess Int. 2:32-66.

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