Co Vaiss General principles and regulatory considerations: specifications Christopher M. Riley*, Laureen E. Little** { * Riley and Rabel Consuiting Services, Maryville, MO, USA, * Quality Sercer, Pan Desert, CA, USA CHAPTER OUTLINE 2.1 Definitions : 2.1.1 International guidelines... 2.1.11 Drug substance. 2.112 Drug product 2.1.2 Pharmacopelal monographs and general chapters, 2.2 Specification Setting Prot0SS.nnnm 2.2.1 Selection of attributes and critical to quality attributes 2.2.2 Development of quantitative acceptance criteria 2.2.2.1 Population mean, sample mean and the “target” 22.22 Capability analysis 2.2.2.3 “Shift happens" 2.2. Calculation of quantitative acceptance criteria 2.2.4 Release and stability specifications 2.2.5 Shelf ie ..esneninnsssninnnnninnnnnni 7 2.2.6 Contribution of anelytical variability to overall process variability 2.3 Cestfcates of Analysis, Trending and 00S Results. 24 Specifications 2.1 DEFINITIONS 2.4.1 Intemational guidelines ‘The main guideline published by the Intemational Conference on Harmonization (ICH) covering the specification of new chemical entities (NCEs) is Q6A: Specifications: Test Procedures and Acceplance Criteria for New Substances and Drag Products: Chemical Substances. The corresponding ICH Guideline covering biologicals is Q6B: Test Procedures and Acceptance Criteria for Biotechnological! Biological Products. Additional information on specification setting can be found in other original ICH Guidelines in QU (Stability), Q3 (Impurities), and Qé (Pharmacopeia). The more recent ICH Systane Subs nd Prec: i dary GI LED 9 Slop 0014 Benmrs irr mere10 CHAPTER 2 General principles and regulatory considerations: specifications Guidelines, Q8, Q9 and Q10 also have important implications for specification setting, especially within the contest of the application of Quality by Design (QbD) to process optimization/alidation and formulation development; as well as to analytical method development and validation. The QbD ‘concepts (in Q8, Q9 and QIO) and their application to pharmaceutical analysis ae discussed in detail in Chapter 3. A fall listing of all the ICH Quality Guidelines and reteyant Multiciseiplinary ICH Guidelines is piven in Table 21, ‘According to ICH Q6A, a specification (singular) contains three elements: a list of tests (or attributes) references 10 test methods and acceptance criteria! Both guidelines (Q6A. and QSB) inguish between Universal Tests, which ate requited in any new specification for @ new drug substance or drug product, and Specific Tests, which should be determined, on a case-by-case basi, depending on the natute ofthe drug substances or drug product. The Universal Tests for both new drug substances and drug produets are: + Description + Identification + Assay + Impurities Representative deug substance and drug product specifications of the fictitious drug S-(+) xenplifir mesylate (Exemplif™), Exemplii ER 200 mg tablets and Exemplifi 1 mg/mL oral solution are shown in ‘Tables 2.2-2.4, respectively. The relevant drug substance end drug product characteristics are as follows: 2.1.1.1 Drug substance ‘Salt form: mesylate (methanesulfonste) Molecular weight: 275.55 Chirality: ($)-CH): single chil conter Solid state: form HT (ive known polymorphs) “Aqueous solubility: 1 mg/ml. (pH 3.2) “Moisture sorption: non-hygroscopie Recrysallization solvent: ethanol: hexane (5:95, vi) 2.1.1.1. Impurities Process-related impurities: St, 82, $3 Degradation products of xenplivir: S4 2.1.1.2 brug product Daily dose: 400 mg Impurities: Degradation products of xenplivie: S4 and P1 Dosage form 1: extended release 200-mg tablet (Exemplifi™ ER) Dosage form 2: aqueous oral pediatric solution (Exemplifi™ Oral solution 10 mg/mL), containing (0.1% each of methyl- and propyl parabens (as preservatives), Gl volume 200 mL ‘he terms “neceptance Grteria” and “speciation” are often used Inerhungeably, However, aovording 1 ICH QEA nd (Q6B they are different, Specification refers te the entre docament. Aecepancecritetia refers to a specie attibte12 CHAPTER 2 General principles and regulatory considerations: specifications: “Table 2.2 Suggested Drug Substance Specification of the Fictitious Drvg, Xenplif Mesylate™ Xenplifir Mesylate Specification Test (or attribute) Method Acceptance Criteria Chapter Universal tests ‘Appearance: ‘SOP 001.08 Wile ofthe sok 5 Identication| FTIR: Tia 002.00 ‘Conforms to reference 3 specttum Assay HPLO: TM 003.08 98,0-102.0% 8 Impurities si PLO: TM 008.08, NMI {} 0.20% 6 $2 NAT () 0.26% 8 83 NMT (33 0.25% 6 84 NM (<} 0.20% 6 LUnspeciiost NMT (<) 0.10% 6 Total NMT (2) 1.50% 6 ‘Specific teats a Hof 1% aqueous solution SOP 005.01 28-80 (Chia identity Optical rotation; “750° to +75.0° 10 TM 005.03 (Chie put HPLO: TM 097.08, NM (3) 1.556 10 Fexenivie Meting point USP <74t> o Pokmorphic form XRPD: TM 017.02 Conforms to 9 rofetenco sitractograrn | Weter content Karl Fisher tation NMT (3} 0.8% 1" USP Coaity of sotution SOP 002,04 Conforms to SOP 002.07 Ethanott GO. TM 098.01 20 ppm 6 | Hexanet USP <467> 290 pm 1 Methanesutloric acid Go: TM 006.0% NMT (3) 4 ppra!! 6 organic impurities USP <231> CConferms 10 USP a Mexobial ts USP , <82> <1i11> Conforms to USP 15‘Table 2.2. Suggested Drug Substance Specification of the Fictitious Drug, Xenplitir Mesylate* (continued) Xenpilitir Mesyiate Specification Tost (or attribute} Method Acceptance Criteria Chapter “Assumes US cubmisin of apptcation er nica tis or maratng auharzaton appcaton ‘gesumes assay and ipustis are measured by tho sane HPLC mete (S88 Chae 9, "Routing to CH 9A), elt or unspacited mpuri is aqua tothe applicable denteation ies, whichis eters by te daly dove is case 409 ma) (see Chapter 8. “hccarang to 1H OS) eres 2 Clas 3 Seve’ an spse ins ar que. However, in ths eis exams the | etnanal 8 corro 020 pm to minnizeraacton with matarasuloric acto produce chane methanesuforte fkonn ‘putegen (co aso Caer) "Hezane sa Cass 2 alent athe Sts dtated by ICH QBOFRS. "Nip tnt matnanassone ass rita y re mas daly nate of acm han (=) 1.8 ey: (oe ao Chapter 6. "Breousy known ae oany mat" San aoptanoo iter of ardor to USP" proered l a stg f th actual mits because or wl regua a change tothe seelicadon "assures assay ard inpuros are measured by fren HPLC matics (sve Chapter 6 Fie Fourrsrensirm hare Spectoscopy HPLC: High Perfomance Ligad Chrematsraehy anges fa USP general ‘A survey of the principal methods and technologies used for the Universal and Specific Test Methods is discussed in detail in various chapters in Parts 2-6. 4.2 Pharmacopeial monographs and general chapters “The 1906 Pare Food andl Drug Act defined the United States Pharmacopeia (USP) asthe highest legal athority forthe quality control of pharmaceuticals in the US. The United States Pharmacapeia and National Formulary (USP-NE) contain monographs for drug substances, drug products (USP) and ‘excipients (NF); and general chapters (designated by the parentheses < >), Similar legal authorities ‘exis for other regions such as the Iapanese Pharmacopocia (IP), the European Pharmacopoeia (PhEut Or EP) and the British Pharmacopoeia (BP), An interesting difference betwcen the USP and mest of the other regional pharmacopeias is that, whereas the USP is independent of the Federal Government, ‘most other phartnacopeias are governinental organizations, Another important difference between the USP and some of the other regional pharmacopeias is thatthe USP contains monographs on drug products and the others, wth the exception of the BP donot ‘The format of monographs in the pharmacopeas is somewhat diferent from the information in regulatory documents such as the Common Technical Document! (CTD, ICH M4). For example, the monographs in the USP contain information on Specific Test Methods unique tothe drug substance, drug product and excipient in question, Methods already in the general chapters are described outside the monograph, ‘The details of all analytical methods in the CTD axe listed separately from the specification elsewhere in the investigational or new drug application "the Common Techelcal Document (CTD) and its counterpart the Electronic Common Technical Document ave the ‘harmonized documents used fo New Drug Applications (NDAs) and Marketing Authorization Applicaions (MAAS) inthe ICH regions: US, EU and Japan14 CHAPTER 2 General principles and regulatory considerations: specifications Table 2.3 Suggostod Drug Product Specification of the Fictitious Drug, Xenpliir Mesylate* 200 mg Oral Tablets (Exemplifi ER) ‘Xenplific Mesylale 200 mg Oral Tablets ‘Test (or attribute) Method Acceptance Criteria Chapter Universal tests ‘Aepenrance 0P 097.08 ‘White caplts 3 ienttcaton vy: Ta 010.60 Canoes to reference spactum tention tina of man HPLC: TM 010.00 oak wth 536 of pk 5 Frstandrd solution | Assay HPLO: TM 003.031 90.0-110.0% 6 Tmpurtios PI HPLO: TI 017.01 8 Pe NMI (2) 0.7% 8 sit NMT (3) 1.0% 8 UUnspacttod NWT (=) 0.2% 6 Toss NWT (5) 2.6% 6 ‘Specific tests Drug relenso USP 2 Method! TM: 01308 Redaased at = 45.0-85.0% Relooced at 10h NLT ©) 60.0% Content unfomity PLO: Tw.c09.083 onions to USP 6 Microbia ets USP , Confoms oust 8 62>, " “Assumes US submission of apacaton fr chal a or marking autbrzaton apptcation. ‘assumes assay and npn are maasered by afer HPLC medias s52 Chap 6) 's4i¢a degradation prodict and should ba mentored fr acergrate nthe dria product andin ta chug substance} 91, 2 03 ae rovase knpuatine fhe cg eubetarce and noe! nat he mace hie ug erect ie Chae 8 ‘orci atsbutoe of nan-toe sharmacoutica ross. “An accepiane enero “conors to USP” pratared oa fst of te sper ut roqure a chango to specicton, stu because changes b USP generat Being the highest legal authority in the US, samples seized in the Geld by the authorities such asthe Food and Drug Administration (FDA) must meet the requirements of the pharmacopeial monograph, if such a monograph exists" If such a monograph does not exist, the next highest legal instrument is the specification inthe appropriate regulatory filing (e.g, New Drag Application, NDA), Farther details of the pharmacopeias as they relate to specification setting, including Pharmacopeial Harmonization, are discussed in more detail in Chapter 4 Wheveas seized sample must meet the veevant regional pharmaoapeial requirements when texed hy the reglniony ‘agency, i eed not have be tse by the fr using the aplieable USP pharnacoplal monograph or genta capers {less eo sated in relevent reglaory fling) eases14 — CHAPTER 2 General principles and regulatory considerations: specifications Table 2.3 Suggested Drug Product Specification of the Fictitious Drug, Xenplifir Mesylate* 200 mg Oral Tablets (Exemplifi ER) Xenplitir Mosylate 200 mg Oral Tablets ‘Test (oF attribute) “Method Acceptance Criteria Chapter Universal tests. “Appearance ‘SOP 001.08 Write capiets| 8 Iantiication uv: TM a10.00 CContorms to reference spactrurn tention tina of ma HPLO: TMo10.00 eek witin 5% of pea 5 In standard solution Assay HPLC: TM 008.031 0.0-1100% 6 Pi HPLC: TM 011.01 NMT {3} 0.4% 6 Pe NMT (s} 0.756 6 sal NMT(S} 1.0% 6 Unepectfiog 02% 6 Total NMT (<} 2.5% 6 Specific tests Drug release USP <724> Foleaved at tn=NMT (<} 10% 12 Method: TM: 013.08 Feleasec! al 5 h = 45.0~55.0% Foleased at 10h NLT (>) 90.0% Content uritrmity HPLO: TM 093.03 CGonfarms to USP 6 Merobial its usp <61>, Conforms to USP 15 82>, <1i1t3! “Assumes US subisson of apical ke cca tas or marelng uration appeal ‘femumosaseay and ercuris aro measured by aferent HELC mothods (cee Chast 6 ‘tis eatin grocct and aud be monitored faperopraa te dug pec and tho chug substan) St, $2 ‘nd ae process mutes of he cry substance and need na be montorad nthe chug proc (se Chapter 6) sorobtstanves of aoe pharma prods “an scceptane cai of “contonns t US” spread fo 2g of he actual Ils Because changes h USP panera chapter ui equta a change otha sceccati Being the highest legal authority in the US, samples seized in the field by the authorities such as the Food and Drug Administration (FDA) must meet the requirements of the pharmacopeial monograph, if such a monograph exists." If such a monograph does not exis, the next highest legal instrument isthe specification in the appropriate regulatory filing (e.g. New Drug Application, NDA). Further details of the pharmacopeias as they relate (o specification setting, including Pharmacopeial Harmonization, are discussed in more detail in Chapter 14. ™ Whereas « seized sample must meet the selevant regional phrmavopelal rapiremeas when tested by the regultery agency, it need not have heen tested by the finn using the epplicable USP phamacepeiah monograph or general chapters (unless 9 sted in telovant regulatory Bling)Table 2.4 Suggesied Drug Product Specification of the Fictitious Drug, Xenplifi Mesylate* 10 mg/mL mg Oral Solution (Exemplifi Oral Solution) enplifr Mesyiate 10 mg/mL Oral Solution ‘Test (or attribute) Method Acceptance Criteria Ghapter Universal tosts | Appearance SOP 001.08 ‘Gear, colorless saluton 5 Idontiication Uv:TM 010.00 Conforms to rerence spectrum HPLC: TMot0.00 Fetenton tine of main peak within 5% of paak Fr standard solution aaa 2.2 Specification setting process 15 HPLC: TM 008.03" 80.0-110.0% Gian HPLO:TMoT1.01 RMT) 08% 6 Pe NWT (3) 07% 6 sit Nat (=) 20% 6 Unspecified Nur (<)0.2% 6 Tota NUT (=) 3.5% 6 Specific tests Deliverable woume USP <608> ‘Conforms to USP fH SOP 006.01 5-82 Methy| parabens (0.1%) HPLO:TMO18.01 850-1159 16 Propyl parabens (0.195) 850-115% Microbial its USP <61>,<62>,<1111>" Conforms to USP* 6 g ral orities opeial legal NDA). sopeial eultory chapters “assures US submisian of application for cca bas or maraing a ‘assumes sseay ana wreurites re measured by ciferent HEL. metre (S68 Cpt 6) "sais a cradatin pout ard stoula be mantored is concentration hereases oer tre) in hed produc ae wel as the ug stan, St, S2 aed St ro prooass aus of Wa cg sketance ane nen na be mowtersd Uh drag ‘product 00 Chapir 6). Sites ati es of non sterte pharmaceutical pods “Yar accaclance cra of “contrms to USP" sprefered toa leing of tho actu ats becauso changas n USP gana} lupe wal equtea change tothe specioatbr, 2.2 SPECIFICATION SETTING PROCESS 2.2.1 Selection of attributes and critical te quality attributes ‘The attributes (tests) in the specification fora new drug substance or anew drug product are selected on the bass ofthe regulatory requirements prescribed in ICH Q6A or QOB for chemicals or biologicals, respectively (ie. Universal and Specific Tests). The eriical quality attributes (CQAs) are a subset of: = Ta 16 CHAPTER 2 General principles and regulatory considerations. specifications the attributes in a specification that if not tightly controled may adversely affect the efficacy and/or safety of the product. The emphasis on identitying the CQAS arose from the moe eeeatly published TCH Guidelines, Q8, QP and QIO. For example, dissolution or dissolution rate can be {COA for 4 sustained release or controlled release oral formulation, particularly if the active drug substance is ‘ highly potent compound, Once identified, the appropriate ranges for CQAS are defined (e.g, by design of experiments, DOES) as part of the QhD development programm (see also Chapter 3). The CQAs ean also form the basis of a Comparability Protocol included in the CTD to define the fling requirements for any post approval changes (0 the Active Pharmaceutical Ingredient (API), formulation or manufeoturing Processes, The selection of the regulatory (ICH) attributes and the CQAs will be discussed in more detail in subsequent parts of this book, 2.2.2 Development of quantitative acceptance criteria Although this is not a book on statistics, knowledge of the statistical principles involved is essential to amore complete understanding ofthe process of specification setting and method validation. The basic: Principles are summarized here and in Parts 2~6, Readers wishing to learn more on the subject are Fefeired to several useful texts, 2.2.2.1 Population mean, sample mean and the “target” Data come from an underlying population of possible results. The distribution of the data in the Population may be known (e.g. a discrete distiibution like the binomel or continuous Like the normal) ©F unknown, The underlying population distributions most cornmon in analytical chemistry always have an overall mean denoted by 4 which is the center (rst moment) of the distribution und a standard ‘deviation denoted by o which indicates the spread of the data about. In almost all situations, and ar unknown so they need tobe estimated froma sample taken from the dstibution, Data are generally collected to make a statement about ps and/or g. For example, one may want to Know the mean of 4a batch (4) or the provision of an assay (a) or want to compare two methods, that isthe two method population means (are jy and 2p equal). ‘The population mean is estimated by the sample mean, given by: 21) wre is the sample sie The poplavon standard deviation i etna by sample Sandan deviation, is ven by: _ (Trae Veniae tice @ Equation (2.2) uses n—1 instead of WV so as not to derive a “biased” (overestimated) value of the Population standard deviation, One distribution that is commonly assumed is the normal or Gaussian distribution, The distribution (y) of the measurements (x), centered at «with standard deviation o, is doseribed by:al L| 2.1 Definitions 13 Table 2.2 Suggested Drug Substance Specification of the Fictitious Drug, Xenplifir Mesylate* (continued) Xenplfir Mesylate Specification ‘est (or attribute) Method Acceptance Cri ‘Chapter “Assumes US submission of appfcaton fr crcl uns or merkatngautortzaton appicatin. | assumes assay ara inputs are measured by tho came HPLC mete (see Cate "Aacerding to CH1Q2A fi) th ia forucecisimpuntess era ate appcatie Senco fehl, wbichin tunis eterinad byte cy dase fst cas9 409 mg) eee Caper 8 “econdng to 1 QS), tharos a Clase @savent and aps is are requ. However, inthis ftnous expo tha then cotated fo 20 xm to mhizerescitcn with mathanesslon aoe produce ethene methanenart air ‘uszgon) (e050 Grae. "Horano i Class? solvent athe Sits tated by KH BCR kt mthanesstore cis inte byte maxi daly Mae of mot me than (5) 1.8 gy; 00 abo Cac 6 ‘Previous known 36 “ety mela” "an evegpiance cea of “carforms to USE" is protarel to. ting o he acu is becase change lo US gover her witroqute a charge fo fe apciiaton, “Assumes assay and inate aw measured by deren’ HPLC method sce Chater frie Fourarsransiom hired Spoctoscopy HPLC: High Pefrmanes Liga Chemetogapiy A survey of the principal methods and technologies used for the Universal and Specific 1 Methods is discussed in detail in various chapters in Parts 2-6. 2.1.2 Pharmacopeial monographs and general chapters ‘The 1906 Pore Food and Drug Act defined the United States Phaemacopeia (USP) as the highest legal authority for the quality control of pharmaceuticals in the US. The United States Pharmacopeia avcl National Formutary (USP-NF) contain monographs for drug substances, drug products (USP) and excipients (NF); and general chapters (designated by the parentheses < >), Similar legal authorities «exist for other regions such as the Japanese Pharmacopoeia (JP), the European Pharmacopoeia (PhEur (or BP) and the British Pharmacopoeia (BP). Au interesting difference between the USP and most of the ‘other regional pharmacopeias is that, whereas the USP is independent of the Federal Government, ‘most other pharmacopeias are govemmental organizations, Another important difference between the USP and some of the other regional pharmacopeias is that the USP contains monographs on diug products and the others, with the exception of the BP, do not ‘The format of monographs in the pharmacopeias is somewhat different from the information in regulatory documents such as the Common Technical Document" (CTD, ICH M4). For example, the monographs in the USP contain information on Specifie Test Methods unique to the drug substance, «tug product and excipient in question. Methods already in the general chapters are described outside the monograph. The details of all analytical methods in the CTD are listed separately from the specification elsewhere in the investigational or new drug application. "The Common Technical Document (CTD) and its counterpart the Blectonie Common Technical Document ae the harmonized documents used for New Drug Applications (NDAs) mug Marketing Authorization Applications (MAAS) fh the TCH regions: US, EU and Jopan,2.2 Specification setting process 17 \ for = ents, i ae ales ae | a tare: aa mal) : Distribution of data (u--x) in units of ¢, 1 1.96(¢) to + 1.96(0) 4) {In many analytical methodologies a skewed or non-normal distribation is seen when caleulating the ey reportable values, This is a common occurrence for methods for biopharmaceuticals, which are calculated using a log scale for the underlying dose-response cucves. It is a common practice to perform a transformation to normalize the data. Such datasets are often said to be “log-normally distributed". ‘Typical transformations include; log, In and Box-Cox transformations. Biological Potency assays, liter-based assays and many Enzyme-linked Immunosorbent Assay (ELISA) meth- a ‘odologies require transformation prior performing any of the following calculations, Therefore the previous statistios discussed above are calculated utilizing a transformed date set ‘The geometric mean (GM) for the In is calculated by: of the asian oM= Avenge 25) where Average equals the average of the natural log responses. The geometric relative standard deviation (GRSD) is calculated by GGRSD = 100 x (€* ~ 1)% 2.6) 23)fm 18 CHAPTER 2 General principles and regulatory considerations; specifications Figue 2.1 also shov thatthe greater the spread in the data the (i.e. the larger the value of the Sian deviation), the lesser the fraction ofthe data that is contained within a specific range, For Eximple, suppose a potency assay has a mean of 100 witha standard deviation of 1. Then 95.5% of the jndividual results would fall within two standard deviations of 100 (98-102) Ithe standard deviating Fay oubled (instead of 1), then 95.5% of the individual resulls would lie between 96 ond 104. Onin 68% would lie between 98 and 102, ‘The statistics frequently used to desribe the error associted with the repeated measurements of the mean is the standard error of the mean (sem), which is given by. sem = Fi en It follows that 95.5% of sample means will fall between: wo t96() reese eet of formulating at 95% oF 925 of the target onthe effective shel! ie of the pci ‘The closer the assay value is (othe LSL the sooner the assay value will go out of. specification, reducing the effective shelf lie 2.2.2.3 “Shift happens” Rerite the bos efforts of process engineers and formulators, the mean of any comercial pharma: Seutical product will shift overtime. A trend (gradual or immediate) to lower or higher valuve ofthe fa Cam, overtime, reach values as high as w+ 2a. ‘Therefore, the process must be monitored over ie 68 by the use of contol charts and the mean recentred if posible. Shi inthe mean by such pace Um can have significant effects on the “defect rate” or the rate of rejection of commercial batches. The effect of mean offset is llustrted in Fig. 2 3a) and (b) Process variability can also increase overtime, due to lack of process control or control of key Cn ae ing to an increase in the probability of the batch failing to meat the acceptance crterg, Gs 230). Both those cases demonsrate the importance of monitoring the procese closely using tenol charts, (8. Fig. 2.3) and recentering the process andor adjusting the process te elaine trends and/or maintain or recuce the variance (a). 2.2.3 Caleulation of quantitative acceptance criteria insisting to consider the use of capability analysis and the principles discussed above to st the cas aeePtance criteria for in-process and final produc specifications. However the lech of a gine “state ofthe stondard deviation may make this approach unreliable. The lack of reliable eeuwae ot20 CHAPTER 2 General principles and regulatory considerations: specifications fiw | |r104 | | | Tonst=a= 1a fond HE 95% { te. 292% | og Seve Stability spectcation "I imit = 90% —al Figure 2.2 Effecton efectve shel i arian reductal the man asoy valu a) anda hale opcoicaion limits {SU of etner 85% oF 92%, for 2 product with degradation rele or ee Per month, the variance of the processor product arises from the fact tha the standard deviation is estimated from only a few critical batches (generally pivotal einial balenes “registration” batches). ICH Q6A, and OGD suggest that accopance criteria be ston the basi ct te there registration batches another Fepreschlative batches, which may be a very small number, Additionally, the FDA secks to establish SPetiicatons based upon clinical experience. This repre tents a challenge for the industry, even with the advent of QbD approaches which will inerease the aaa vs and understa : 2.2.4 Release and Stability specifications jan breeding imitations notwithstanding, eapbily analysis may have some utility when setting the vale, cePtance criteria forthe finished product (and in-process samples) and the width of the target ‘alues at product release to ensure thatthe product does nen £80 out of specification prior to expiration Frew of the USL and LSL (ie. the Acceptance Crtria tke ‘Release Specification) can influence {he potential shelf lite of the product. Figure 2.4 shows that the lighter the range of USL and LSL, the Stoner the potential shelf life. By convention, the Acceplane ey iteria for assay (poteney) in the ‘release specification are typically 95-1054 end the6 2.2 Specification setting process 21 (a) sem oi 1 scan [6 4 ‘ | ‘ vane : emt vii i (b) increase Process Vrity A from (o) TQ6A Fother i anne | ablish : swith : won ss and : ter of i ween | ralysis call svete ing the target ration i BL the 4 riouRe 2.9 rt ‘ Contra chart showing the effect ofa) slant standard cevton and increasing standard aa : deviation (constant centered mean) during routine commercial production, ‘hat the: be ae ication : ssultin : severly true for a pharmacopeiat monograph, By contrast, i the HU, separate specifications are ‘ required at release and on stability. However, in the absence of a regulatory release specification, Inthe tighter “in-house” release specifications are generally used to ensure thatthe product will mect the is also regulatory specification thoughout its shelf life. If this is done, it should be noted that the US22 CHAPTER 2 General princinies tions: spectications and regulatory considera us. Alert nit Alt lnt forthe monitoring stably data using assay a5 an exami) fegulators may treat the determining if a reported yal Investigation. Tychouse” release specification just tke any label Specification when ve i an out-of specification (OOS) and require © thorough, formal OOS: 2.2.5 Shelf life A shel if between 18 Storage at room temperature is prefered to ensure Iminageable inventories adtonal (all wolecle)phatmeceualy, Many parrareertcls hive restated oF hosen songe fegarereP of the newer bio. Shaner sei a SHA sll henpies hive exenely ate ee Shorie than 2 weeks, sabi es refgeraton temperate are gency see Special cases or where the “sayy ol the ott does 0 alos room tempera wore he ‘months. mate ncay a simulated dad esiged 10 demons Ie ease Shelf fe Gn this cece ant er aBUt ih a degradn rate of. per ma ae per month a 25 °¢7 RHO C7SSRH Data wrest fr cel ined on months 25 “C60 misihnce Somat 40°C7S REY and aayand accong ee cline Q1A(R2), Note The canes ash fe the esimaton of selfs Tape Batches wil be use, 24 non ar 2 CISERY we so how fr iseatne eee values at 12, 18 and rong a 2 SCUSOSRH wee cata by Lar exiare ee 0-9 monty data. Iris Lie a 20 months Fig, 2.5) based onthe intersection of a extrapolated data rete ee cussion there will be determinate errors inthe Deepal Therefore, amore statistically valid appronce= EE 2.2 Specification setting process 23 ns 4108 |,_Bealsine Exirapoleted | vaiise values : = Ff SO a a | : 0 we [Proments, ' os ee : Of eeie terete lie irtpetaira | Time month); | i : - Shalt Lite=181 montne Bhatt Lite 19.8 months (based on where Glo! (based on inet extrapolation predited (Assoy| intersects 90%) To Assay 30%) when ven riouRe 2.5 Calculation of hee (bed on stay) fer a produ wha degradation rate oF 0.5% per mond and 5% per tmoth al 25°CISD%RH (cece) and 40 °C/754RH (uate), calculated by Incr extapuation of 25 °C60% BH dat; andthe lover 95% confdence Interval of iear extrapolation of 25 °CGOLRM dal, ensure In contrast to small molecules, bopharmaceutical shel-ifecaleulaions ae not usualy calculated Many based upon sceeleraed temperatures 1: has been shown thatthe complenly of the active ingredient + ioe andthe requirement fora specific 3-dimensional structure is not conducive to using various models, seeks. Sch asthe Arenas equation, to estimate real-time storage stability, Therefore oly real-time storage sre the data at the proposed storage temperature are typically accopted by the regulatory authorities for establishing the self life. I has been proposed to the World Health Organization (WHO) and other in this ovement egultory autbores that addtional real-time datapoints for biophanmaceutcal products 28°Ci be collected than those recommended by the ICH Guidelines for the calculation of shelf life. 260% i ae 2.2.8 Contribution of analytical variability to overall process variability Band There are three types of errors that contribute to analytical results: gross eror, systematic errors a. Itis i (determinate erorso bat) and random errors (indeterminate ervors or precision). 1s important that data i none ofthese errors contribute significantly to the overall vatablity of «processor proc! attibute; inthe : otherwise the method wil be ineapable of detecting differences between batches or changes within proach a batch. Gross errors (such as failing to adjust a solution to volume, or dropping a flask) should be 195% : detected during an investigation into an aberant result nd corrected. Lee ‘The contributions of random or indeterminate errors have been discussed in detail in the previous life is q sections, Delerinae eros (bas) should be eliminated during method development and her absence confirmed during method validation (Chapter 4), The contribution of the random errors in the24 CHAPTER 2 General principles and regulatory considerations: specifications pe eriy Messuremen (yyy) t0 overall variability (oc variance) of an alibi Tho ogee can be determined from the prineiple of propagation of ence Casas + 3 i io cher @.13) fal aanenstted by the following example. f we assume, ss dseussed in Seaton 2 24, the fd te at Seviton ofa press eg assy) is equal to half he iforses Bane the mean the arate (OF upper) specification limit (ie. 5%) and the standord deviate (cepeatabilty) of peg hy method i 1.5%, the contibution of te remaining thet woah variability» asay is siven by: pear arectee oer = Cent ~ Fal y ct 14) Sires = VETS = 4.72% 1s) {inthis example, Eqns 2.14) and (2.15) predict that although the analytical method contributes 309% athe overall variance (variability) ofthe measurement (a2 nisteat/ Ma) It Contibutes less than 6% of Cans anterd deviation (028/500). The contribution of ance ee expanded further i Chapters 3 and 6, 2.8 CERTIFICATES OF ANALYSIS, TRENDING AND 00S RESULTS eames: obvious use of drug substance and drug produet specifications are in the retease and stability testing of drug substances and drug products associated wah stalin conducted under current Good Manufacturing Practices (GMPs, clinical tials), Good Laboratory Practices (GLP, nonclinical Studies) and “unofficial” experimental studies Gif requ Quality Assurance (QA), is issued, Release of a atch forelinieal an ees Gf ie manufacturing batch record and, depending an ihe phase of develop Verification of the raw data, Strict interpretation manvfacturing batch records is not requined —| ‘reagent manafacture occurs in a GLP envirom procedure (SOP) and a routine study documen ‘can take the place of a batch record, Although the practice is common 3S accompanied by review prment, partial or complete of the GLP requirements reveals that review of the However, it is strongly recommended. When testing or wment, the QA group often creates standard operating « for collecting typical manufacturing information. This specially by Contract Manufacturing Organizations (CMOs), to issue @ CoA after testing at each stabi reat bles, which ae updated after each stability time point, Irene treet stabi {esting of remmned retained samples) is conducted as part of following testing ofthe frst sample pulled after the i (GLP) study report is especially critical for samples ints of the specication. Otherwise a false OOS result may oeoue ieated OOS verified by a formal sd nicsesna... ae 6 2.4 Specifications in early development 25 wean a investigation led by QA will result in batch rejection or recall of a batch from the clinie or from i commercial distibution. Vaid reasons for analytical erors and rejection of an OOS result are bias nd ; gross errors: analytical imprecision is not. Examples of gross errors include: incorrect following of @.13) 4 procedures, ineorrect instrument setting, instrument failure, and failure to meet system suitability. As : Giscussed previously, analytical bias should be detected and eliminated during method development 4ythe a and/or method validation. However, the OOS investigation may reveal a new source of ertor not mean 4 previously detected during method development and validation, In this case the method should be 'y) of ‘modified and the appropriate: components of the method revatidated, Graphical trending of stability say is Gata (ee contol chars, Figs 2.3 and 2.4 is essential fo anticipate potential future batch failures and stability failures and appropriate rermedial steps taken, Figure 2.2 demonstrates the importance of controlling the Variance of the measurement for a particular attribute when the results approach the er) : limit in the specification. Otherwise, an OOS may be generated on the basis of chance. ‘Aleris limits are also useful (Fig. 2.4), Following the well-known case of the United States vs Barr LLaboratories.* the possibility of generating an OOS on the basis of chance is increased by the fact that as) ‘any result containing a single value outside the acceptance criteria is considered OOS, even if the mean is within the allowable limits. This further emphasizes the importance of trending batch history and 820% stability data and the application of alert Fimits, 6% oF Tt is important to note that the US vs. Barr Decision also teats biological poteney assays ver in differently than physical/chemical methods for small molecules. The USP General Chapter <111> specifically states that because of the higher variability of potency assays itis a standard procedure to calculate reportable values based upon more than a single assay run and that these averaged values may include individual values that are outside the specification. These individual values are ‘not treated as OOS results as long as the average potency estimate is sufficiently precise as defined ability ; in the standard test method or SOP. Good linicat lee Eee eae oe ocean ESTEE a ‘ite 2.4 SPECIFICATIONS IN EARLY DEVELOPMENT alan "he previous cussions have focused priory on ate development speiction and speetions ee 4 to be included inthe marketing dossier. Very recently a working group of an industry grovp, the IQ of the 3 Consortium” has published an article on “Early Development for Small-Molecule Specifications. An tee Tdusty Perspective”, This article emphasizes the Fat that very litle information may be available to aa support firm specifications for the dig product and the drug substance in early development See : “Therefore, “early development specifications should... focus on thse fests and acceptance criteria detertned to be critica for the control of product quality and supported by preclinical {safety and sa : ‘arly clinical sofery studies.” In that paper, the authors propose standardized carly phase tests and a cceptance criteria for both the drag substance and the drug product, They also differentiate between re test results that are (0 be reported to the agency at relense and on stability from infernal tests and ped acceptance criteria that are not pert of the Formal specifications The paper diferntiates between the a ‘aly nonclinical batches where there ate generally no formal specifications, and first in man bales, where the sims ofthe former ae amples + Ensure thatthe correct dosage is administered inthe noalinical studies oct, + Determine the correct potency value ofthe drug substance to ensue proper dosing of the animals formal : + Quan fy impurities for nonclinical qualification (establish the initial impurity profile)| 1 i 26 CHAPTER 2 General principles and regulatory considerations: specifications Table 2.5 Proposed Specifications fr Clinical Dug Substance In Early Developmont 7 Proposed Release Internat Stability. Attribute Acceptance Criteria Testing? Testing Deserition ange of coor + - + description ‘eniication Spectrum conforms + - - torolerenca Counteron Roport raul + - Assay 97—103% on + - antydrous, solvont-fe® bass Impurities {ncdvicuol NMIT 1.0% + + Tola NM 3.0% Chicstimpurty NAAT 9.0% + + + Festival [CH 036 or other + + - solvents justo tits for ‘sokents In fina , synthetic stop ae Mutaganio CHMP Guiceina - + > impuutes (Pet. 8) unig 7 'simpiomontes Inorganic EMA ils (Ret. 0) + 4 ‘impuritos Unt ICH 30 is implemented Weter content Report rasuts _ + + Solid form FRoport resus - + + Parte azo Report results| - + Residue on NM 1.056 S + - ignition rey ar ae tamed ct a rn ekacomen of chase este Wie tn dj banc, along (nay have ergot acceptance cir that aro ther than ta rceroo ects ome Aadasted tom Pe. 7 TR Pape oes on to emphasize thal the inital acceptance criteria fox carly clinical batches are targets {asin the result ofthe intial nontinical studies. They further emphasize the vale of using the es batch of drug substance in both theeaelynonetnial studies and he frstin man studies, in whichesce he ‘wishing €0 team more about this apy powder in a bottle, powder in a capsu Acknowledgment Te authors are grateful co James Borgum (BerpumSTATS) fr his thorough evew ofthis hep | i