可见微粒检验

Visible Particulates in Injections—A History and a Proposal to Revise USP

General Chapter Injections h1i

Russell E.Madsen,a Roy T.Cherris,b John G.Shabushnig,a and Desmond G.Hunt c,d

A BSTRACT This Stimuli article provides a history of visual inspection practices and requirements for parenteral products in the United States.It includes a sampling plan and test for products that have been100%inspected as part of the manufacturing process and criteria by which a product can be considered‘‘essentially free’’from visible particulates.The proposed test alone is insuf?cient for batch release testing—a complete program for the control and monitoring of particulate matter remains an essential prerequisite.The proposal is generally harmonized with the Particulate Contamination:Visible Particles section of the European Pharmacopoeia and the Foreign Insoluble Matter Test for Injections in the Japanese Pharmacopoeia.The objectives of this Stimuli article are to initiate discussion and to solicit public comments that will be considered by the Ad Hoc Advisory Panel—Visual Inspection of Parenterals and subsequently the Parenteral Products:Industrial Expert Committee.The Expert Committee will consider recommendations from the Advisory Panel regarding the proposed revision.

THE NEED TO INSPECT

Visual inspection of parenteral products is driven by the need to minimize the introduction of unintended particulate matter to patients during the delivery of in-jectable medications.Such inspection also offers the op-portunity to reject nonconforming units,such as those with cracks or incomplete seals,that pose a risk to the sterility of the product.The desire to detect these defects at a very low frequency and the randomness of their oc-currence have resulted in the current expectation that each?nished unit be inspected(100%inspection). Human visual performance is critical to the assessment of visible particles.The threshold for human vision is gen-erally accepted to be50m m.The detection process is probabilistic;i.e.,the probability of detection increases with increasing particle size.Analysis of inspection results pooled from several studies involving different groups of inspectors shows that the probability of detection for a single50-m m particle in clear solution in a10-mL vial with diffuse illumination between2000and3000lux is slightly greater than0%.This probability increases to ap-proximately40%for a100-m m particle and becomes greater than95%for particles200m m and larger(1). Many animal studies have been conducted to deter-mine the fate of intravenous particles of differing size and composition(1–4).Most studies have focused on subvisible particles that have a diameter of less than50 m m.The smallest of these particles(approximately1 m m in diameter)are often trapped in the liver,lungs, and spleen.Intravenous infusion of particles larger than the internal diameter of capillaries may be clinically sig-ni?cant because the particles may increase the risk of for-eign particle embolism(5,6).Larger particles generally do not migrate far from the injection site.The most com-mon response observed is the formation of emboli and granulomas.Although they help explain the physiologi-cal response to particulate matter,the large number of particles employed in these studies(e.g.,109particles/ kg/injection)provides little guidance about the risk of de-livering small numbers of particles to patients.

Several reviews describe the effect on patients of par-ticles in parenterals(7–13).Garvin and Gunner were among the?rst to express concern about the effects of particles in patients(14,15).Ethical considerations pre-clude controlled human studies on the effect of particu-lates in human patients.Some anecdotal information can be obtained from studies that involve intravenous drug abusers(16–18).In these case studies,solid oral dosages often are ground up and injected as a slurry.Pulmonary foreign body emboli and granulomas were observed in these patients.Again,the clinical risks of particles admi-nistered in other settings are dif?cult to infer from these observations because of the large number of foreign par-ticles and the uncontrolled conditions in which they were administered.

Even though an estimated15billion injectable doses of medicines are dispensed each year(19),no reports of adverse events associated with the injection of indivi-dual visible particles have been found.Although zero de-fects is the desired goal and should drive continuous process improvement,it is not a workable acceptance criterion for visible particulate matter because of current packaging components and processing capability.The US Pharmacopeial Convention(USP)has adopted the terminology of‘‘essentially free’’to recognize this current state.As we move forward,a more precise de?nition is desirable to prevent misunderstanding and to aid in communication of this important quality attribute.

a Member,USP Parenteral Products—Industrial Expert Committee

b Member,USP Ad Ho

c Advisory Panel—Visual Inspection of Parenterals

c Documentary Standards Division,USP

d Correspondenc

e should be addressed to:Desmond G.Hunt,PhD, Scientist,US Pharmacopeia,12601Twinbrook Parkway,Rockville,MD 20852-1790;tel.301.816.8341;fax301.816.8373;e-mail dgh@ https://www.wendangku.net/doc/ac10833307.html,.Stimuli to the Revision Process

HISTORY OF INSPECTION STANDARDS

In 1915USP IX described the need for injectable com-pounds to be true solutions.In 1916,the National Formu-lary (NF IV )included six monographs for parenteral products and speci?ed the method of preparation,but neither Compendium provided guidance with respect to solution clarity.

The ?rst appearance of ‘‘solution clarity’’and freedom from contaminants for parenterals occurred in 1936in NF VI .A requirement for clarity in injectable solutions spe-ci?ed:‘‘Aqueous ampule solutions are to be clear;i.e.,when observed over a bright light,they shall be substan-tially free from precipitate,cloudiness or turbidity,specks or ?ecks,?bers or cotton hairs,or any undissolved ma-terial.’’

The requirement for visual clarity of parenteral pro-ducts began in 1942.This was before USP’s acquisition of NF and required coordination between USP and the American Pharmaceutical Association,the publisher of NF at that time.The two compendia that were of?cial at the time,NF VII and USP XII ,were coordinated in re-sponse to the need to de?ne and control the quality of injectable products purchased in support of the military during World War II.Together,the compendia intro-duced the term ‘‘substantially free’’to describe the need for control of particle contamination.NF VII stated:‘‘Aqueous solutions are to be clear;i.e.,when observed over a bright light,they shall be substantially free from precipitate,cloudiness,or turbidity,specks or ?ecks,?-bers or cotton hairs,or any undissolved material.Sub-stantially free shall be construed to mean a preparation which is free from foreign bodies that would be readily discernible by the unaided eye when viewed through a light re?ected from a 100-watt Mazda lamp using as a median a ground glass and a background of black and white’’(20).

USP XII stated ‘‘Appearance of Solutions or Suspen-sions—Injections which are solutions of soluble medica-ments must be clear,and free of any turbidity or undissolved material which can be detected readily with-out magni?cation when the solution is examined against black and white backgrounds with a bright light re?ected from a 100-watt Mazda lamp or its equivalent’’(21).Both USP and NF used the same test procedure;how-ever the USP procedure was more rigorous because it omitted the qualifying adverb ‘‘substantially.’’These di-rectives were used by FDA in its role as the Quality Con-trol Of?ce for all pharmaceuticals purchased by the Armed Forces during World War II.On the basis of these requirements,FDA rejected many lots of injectable solu-tions offered to ful?ll government contracts.

In 1947,USP XIII published requirements for clarity of solutions (22):‘‘Clarity of Solutions—Water for Injection,pharmacopeial Injections or pharmacopeial Solutions of medicament,intended for parenteral administration,un-less exempted by individual monographs,must be sub-stantially free of any turbidity or undissolved material which can be detected readily without accessory magni-?cation (except for such optical correction as may be re-quired to establish normal vision),when the solution is examined against a black background and against a light

which at a point ten inches below the source provides an intensity of illumination not less than 100and not more than 350foot candles.This intensity of illumination may be obtained from a 100-watt,inside-frosted incandes-cent lamp operating at rated voltage,or from ?uorescent lamps,or from any equivalent source of light.’’

Following adverse observations during an FDA inspec-tion of Bristol Laboratories,a ?nding of particle contam-ination in ampules was tested in court (23).The FDA inspector,guided by the ‘‘clarity’’requirement as de-scribed in USP XIII ,found particle-contaminated ampules in six accepted stocks from Bristol Laboratories.As a re-sult of this inspection,the company was served with an FDA injunction and request for recall.

Bristol Laboratories challenged the results of the test by preparing a blinded test group of 150ampules con-taining 1.5mL sterile saline.This test group included 38ampules that the FDA inspector had rejected as contami-nated with particles.The case came to trial in 1949.At the conclusion of the government’s testimony,the court granted the defendant’s motion for dismissal.When on the witness stand,the FDA expert witness was asked to replicate the inspection using the test group and passed 36out of 38previously rejected containers.The case was dismissed on the grounds ‘‘1)that the standards in-volved were inde?nite and 2)that the evidence was in-suf?cient to show such violation of the Act as would warrant the granting of the relief prayed for (destruction of the ampules)’’(23).

From 1955through 1970,USP XV through USP XVIII provided guidance about visual inspection of injections.For example,USP XV noted:‘‘Every care should be exer-cised in the preparation of injections to prevent contam-ination with micro-organisms and foreign material.Good pharmaceutical practice also requires that each Injection,in its ?nal container,be subjected individually to visible inspection.’’USP XVI and USP XVII said:‘‘Every care should be exercised in the preparation of injections to prevent contamination with micro-organisms and for-eign material.Good pharmaceutical practice also re-quires that each Injection,in its ?nal container,be subjected individually to visible inspection whenever the nature of the container permits.’’

In 1959,Fed.Std.No.00142,Parenteral Preparations,was issued by the United States Navy Bureau of Medicine and Surgery (BuMed)and became mandatory for all Fed-eral agencies.The standard was applicable to sterile par-enteral preparations in ?nal containers intended for human consumption.The standard was superseded in 1966by Fed.Std.No.142a.The standard provided re-quirements for clarity of solutions as well as limits for visi-ble particulate matter as follows:

Section S6.2.1Clarity of solutions .Applicable to type I,class 1;type II,class 1;type II,class 3;and solutions of dry solids (type IV,class 1).Solutions of parenteral prepara-tions shall be clear and free from undissolved or particu-late matter within the limits permitted in the classi?cation of defects and the applicable acceptable quality level (AQL),when examined without accessory magni?cation (except for such optical correction as may be required to establish normal vision)against a black background and against a white background and

S t i m u l i t o t h e R e v i s i o n P r o c e s s

illumination from a light which at a point25.4centi-meters(10inches)from its source,provides an intensity of illumination of not less than100and not more than 350foot-candles.Some biological products need not be clear and entirely free from turbidity,provided this is characteristic of the product.The clarity standards for such products shall be judged on an item-for-item basis with the characteristic properties of the product consid-ered in each case.

NOTE—This standard was applied as a?nal test to sam-ples of?nished products,not to100%on-line inspec-tion,and the sampling was in accordance with MIL-STD-105.

For aqueous solutions(type I,class1),the‘‘solution not clear’’defect was classi?ed as Major A,Inspection Le-vel II and the AQL(percent defective)as1.0.Therefore,in a30,000unit batch,315units would be inspected;if only7or fewer contained visible particulate matter,the batch would pass the Clarity of Solution Test.Thus,at the time,agencies of the Federal government,including FDA,would deem this level to be acceptable and in com-pliance with the meaning of the USP term‘‘essentially free.’’

Fed.Std.No.142a was amended in1970.It is not known when this standard was abandoned,but the sig-ni?cance of Fed.Std.No.142a is that it provided govern-ment-endorsed acceptance limits for the presence of ‘‘visible’’particles.Parenteral product quality acceptance levels were based on the limitations of sterile-product manufacturing capability at that time.Solomon P?ag, BuMed director in1968,noted,‘‘Within the framework of the technology available on the subject of particulate matter,Military Services have been highly successful in the procurement of quality parenterals’’(24).

Fed.Std.No.142a could serve as a model on which to frame a practical visible particulate matter acceptance level re?ecting the improvement in present parenteral manufacturing technology.

USP XIX,Supplement1,initiated the philosophical re-quirement for a zero-defect quality standard for foreign matter and particles(25):‘‘Every care should be exer-cised in the preparation of injections to prevent contam-ination.Good pharmaceutical practice also requires that each Injection,in its?nal container,be subjected indivi-dually to a physical inspection,whenever the nature of the container permits,and that every container whose contents show evidence of contamination with visible foreign material be rejected.’’This requirement was re-peated verbatim in USP XX in1980(26).

In1995,USP XXIII repeated the requirement for a zero-defect quality standard for foreign matter and particles (27):‘‘Every care should be exercised in the preparation of all products intended for injection,to prevent contam-ination with microorganisms and foreign material.’’This revision returned to the view expressed in USP XIX Revi-sion1that the response to particle contamination in in-jectable?uids must be a graded one.Only one phrase was changed:The previous use of the term substantially free was replaced by the term essentially free.In response to various publications and comments since1980,a graded response to the inspection for visible particles ap-peared in USP XXIII,Particulate Matter in Injections h788i:‘‘Particulate matter consists of mobile,randomly sourced,extraneous substances...that cannot be quanti-

tated by chemical analysis due to the small amount of

material that it represents and to its heterogeneous com-position.Injectable solutions,including solutions consti-

tuted from sterile solids intended for parenteral use,

should be essentially free from particles that can be ob-

served on visual inspection.’’This requirement remains

basically unchanged since the printing of USP XIV(28).

The requirements regarding‘‘visible particulates’’in

the pharmacopeias of countries that participate in the In-ternational Conference on Harmonization are somewhat different,as shown below.

General Chapter h1i in USP31states:‘‘Each?nal con-

tainer of all parenteral preparations shall be inspected to

the extent possible for the presence of observable foreign

and particulate matter(hereafter termed’visible particu-

lates’)in its contents.The inspection process shall be de-

signed and quali?ed to ensure that every lot of all parenteral preparations is essentially free from visible par-ticulates’’(29).No inspection method is speci?ed.

The Japanese Pharmacopoeia states:‘‘Unless otherwise

speci?ed,Injections meet the requirements of the Foreign

Insoluble Matter Test for Injections h6.06i’’(30).Two in-

spection methods are described.Method1‘‘is applied

to injections either in solutions,or in solution constituted

from sterile drug solids’’and contains the following in-structions:‘‘Clean the exterior of containers,and inspect

with the unaided eyes at a position of light intensity of approximately1000lux under an incandescent lamp:In-

jections must be clear and free from readily detectable

foreign insoluble matter.As to Injections in plastic con-

tainers for aqueous injections,the inspection should be performed with the unaided eyes at a position of light in-

tensity at approximately8000to10,000lux,with an in-candescent lamp at appropriate distances above and

below the container.’’Method2‘‘is applied to injections

with constituted solution’’and contains the following in-structions:‘‘Clean the exterior of the containers,and dis-

solve the contents with constituted solution or with

water for injection carefully,avoiding any contamination

with extraneous foreign substances.The solution thus constituted must be clear and free from foreign insoluble

matter that is clearly detectable when inspected with the

unaided eyes at a position of light intensity of approxi-

mately1000lux,right under an incandescent lamp.’’

The European Pharmacopoeia states‘‘Solutions for in-

jection,examined under suitable conditions of visibility,

are clear and practically free from particles’’(31).The in-

spection is described as follows:‘‘Gently swirl or invert

the container...and observe for about5s in front of the

white panel.Repeat the procedure in front of the black

panel.Record the presence of any particles.’’

BASIS FOR THE PROPOSAL

The proposal(see Draft Text for Consideration,below)

is based on Fed.Std.No.142a,which was used success-

fully for more than a decade to ensure the quality of ster-

ile parenteral products delivered to the US government,

and on the results of Parenteral Drug Association(PDA)

surveys that assessed current practices in the inspection

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of parenteral products.Fed.Std.No.142a classi?ed the defect as Major A,Inspection Level II and the AQL (per-cent defective)as 1.0.From the 2008PDA Survey of Vi-sual Inspection Practices (2),the median value for the AQL for Major defects (most often associated with parti-culate matter)is 0.65%.

The proposed inspection conditions have been harmo-nized with those speci?ed in the European Pharmacopeia ,with a recommendation to use a high-frequency ballast with the ?uorescent lamps to reduce ?icker and asso-ciated inspector fatigue.

The proposal uses a General Inspection Level II sam-pling plan,as found in American National Standards In-stitute/American Society for Quality (ANSI/ASQ)Z1.4,as a release test for product that has been 100%inspected during manufacturing and a ?xed sample size of 60units when there is a need to re-evaluate a batch that has been released and is in distribution (33).The re-evaluation,or ‘‘?eld’’sample size is applicable to batch sizes greater than 600units.The 60-sample plan is similar to an ANSI/ASQ Z1.4Special Level S-4inspection with an AQL of 0.65%,covering sample size code letters G (n =32)for batches between 1201and 10,000,H (n =50)for batches between 10,001and 35,000,or J (n =80)for batches between 35,001and 500,000.It has an AQL of 0.60%.A batch with 2.8defective units per hundred would be accepted 50%of the time.For comparison,an ANSI/ASQ Z1.4General Level II inspection at a compar-able AQL (0.65%)would accept a batch with 1.3defec-tive units per hundred 50%of the time.The re-evaluation sampling plan does not require abnormally high levels of retained samples,and,with the exception of powders and/or freeze-dried products,it is nonde-structive.

DRAFT TEXT FOR CONSIDERATION

De?nitions

ESSENTIALLY FREE [Insert at the end of the De?nitions section of h 1i Injections]:

Where used in this Chapter,the term essentially free means that when the batch of Injection is inspected as de-scribed herein,no more than the speci?ed number of units may be observed to contain visible particulates.

Visible Particulates in Injections [Insert as a sub-heading under Foreign and Particulate Matter]:

This test is intended to be applied to product that has been 100%inspected as part of the manufacturing process;it is not suf?cient for batch release testing alone,and a com-plete program for the control and monitoring of particulate matter remains an essential prerequisite.This includes dry sterile solids for injection when reconstituted as directed in the labeling.Other methods that have been demonstrated to achieve the same or better sensitivity for visible particu-lates may be used as an alternative to the one described be-low.

Injections shall be clear and free from visible particulates when examined without magni?cation (except for optical correction as may be required to establish normal vision)

against a black background and against a white back-ground with illumination that at the inspection point has an intensity between 2000and 3750lux.This may be achieved through the use of two 15-W ?uorescent lamps (e.g.,F15/T8).The use of a high-frequency ballast to reduce ?icker from the ?uorescent lamps is recommended.Higher illumination intensity is recommended for examination of product in containers other than those made from clear glass.

Before performing the inspection,remove any adherent labels from the container and wash and dry the outside.The unit to be inspected shall be gently swirled,ensuring that no air bubbles are produced,and inspected for approxi-mately 5s against each of the backgrounds.The presence of any particles should be recorded.

For batch-release purposes,sample and inspect the batch using ANSI/ASQ Z1.4General Inspection Level II,single sampling plans for normal inspection,AQL 0.65.Not more than the speci?ed number of units contains visible particu-lates.

For product in distribution,sample and inspect 60units.Not more than one unit contains visible particulates.

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