Continuous Sterilization

Batch sterilization wastes energy and can overcook the medium
Batch sterilization uses steam or direct firing to elevate the temperature, and then cooling water stops the process and brings the material back toward room temperature. Both the heat and the cooling water are spent with no opportunity for energy recovery. Large volumes should be passed continuously through heat exchangers for energy economy with the hot, treated fluid heating the cold, incoming feed. One method of continuous sterilization injects steam into the medium (no heat exchanger). The medium stays in a loop for a predetermined holding time until the entire medium is sterile. Better heat economy comes from substituting heat exchangers for direct steam injection. Instead of having a cold water stream to cool the sterile media, the lower temperature unsterile media stream absorbs heat from the warm stream, cooling the sterile media. A system for continuous sterilization has a holding coil for detention long enough to kill all of the microorganisms. The medium from a make up vessel flows through the exchanger, is held in the coil, and passes back through the heat exchanger, heating more unsterile medium while becoming cool itself, as it is collected in a sterile fermenter. This design would work only with an exchanger with infinite heat transfer area because there is no driving force for heat transfer as the temperatures for the two streams approach closely. A real design would have another small exchanger to raise the temperature to the setpoint after the main exchanger has done all it can do. There is no need for a cooler before entering the fermenter because it has a jacket or coils for temperature control that can easily handle this load. Heat economy is not important for a small pilot plant unit for continuous sterilization, so direct steam injection is simpler. A heat exchanger is then needed with cooling water to bring the medium back down quickly to a temperature at which it is not over cooked.

Advantages:
Uniform steam requirements throughout the duration of the sterilization Simplified process control Shorter sterilization time means less thermal degradation of medium

Disadvantages:
High demand for steam in a shorter period of time than batch Concentration of media becomes dilute due to steam condensation Since steam is actually dispersed in media, steam must be clean to avoid contamination High temperatures for short times are used in preparing nutrient media for industrial fermentations and in pasteurizing milk, because this causes less damage to biochemicals than more prolonged times at lower temperatures. This exploits the temperature effects on activation energies because bacterial killing is affected by a temperature change more than is heat destruction of biochemicals. Shell and Tube Exchangers

When the flow in a heat exchanger is countercurrent, the outlet temperature of the stream being heated can approach the temperature of the hot stream to be cooled. There is an attempt to show this in the sketch. There are gradients on the shell side as well. The Shell and tube exchanger is not as well-suited to continuous sterilization as the plate-and-frame type of exchanger. Sandwich of Plates. This sketch did not turn out well. Much better sketch by Lawrence Bernstone, 1995 The idea is that the countercurrent flow in alternate sections gives a gradient from coolest to hottest in each plate of the sandwich.

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Converting to Gamma-Radiation Sterilization: An Overview for Medical Device Manufacturers
Reprinted from MEDICAL DEVICE TECHNOLOGY, May 1993 Publication Number 0013 Gamma radiation is becoming increasingly popular as a method of sterilizing disposable medical devices. The conversion from ethylene oxide sterilization to gamma radiation may involve redesigning products and packaging, and establishing a new method of sterilization. However, the conversion process can be regarded as an opportunity to enhance product design, improve processes, and reduce costs. In this article, the authors explain how conversion can be manageably achieved by providing a step-by-step conversion program. INTRODUCTION The conversion process can provide an opportunity to enhance designs, improve processes, reduce inventories, market products more quickly because of immediate product release, and obtain cost savings in products and packaging. For all manufacturers of single-use medical devices, converting from ethylene oxide (EtO) to gammaradiation sterilization usually requires a multidisciplinary approach and cooperation between several functional groups within the company and vendors to the company. This article presents a generic plan of action to achieve conversion from EtO to gamma-radiation sterilization. However, manufacturers must develop a program that is specific to their particular products, resources, and circumstances. Step 1: Product selection The first step in the conversion process is to select the products to be tested for gamma-radiation sterilization and establish priorities. Products with the largest volume and, therefore, greatest potential for cost savings, and those with a high probability of being successfully sterilized, should be given priority in a conversion program. It is at this stage that product and package redesign, and potential cost savings, should be explored. For example, with gammaradiation sterilization, the opportunity exists to develop hermetically sealed packaging with tamper-evident seals. Furthermore, gamma radiation is extremely penetrating, which means that sealed cavities, mated surfaces, and small lumina can be easily sterilized Step 2: Quick radiation preview The second step is to take a "quick look" to identify potential problems. Products may be irradiated at test doses in the order of 25 kGy (2.5 Mrads), 60 kGy (6 Mrads), and 100 kGy (10 Mrads). This simple, low-cost approach will help to rapidly identify components that may become brittle, significantly change colour, or have objectionable odors after gamma-radiation sterilization. Such changes can be expected because stabilized materials will not have been specified at this stage. In fact, these changes should be welcomed because they will provide guidance in the subsequent steps of the conversion process. Step 3: Protocol development Assuming that the results from the previous stage are encouraging, that benefits have been defined, and that there is full support from the management, the third step involves the initiation of a formal conversion program. When undertaking a conversion program, it is critical to develop a formal plan of action, which involves specifying the intended path of evaluation, team-member responsibilities, and the expected results. It is also important to realize that gammaradiation is a well-established sterilization technology and plenty of help is available from contract irradiation companies, material suppliers, and consultants. Step 4: Data collection The fourth step requires manufacturers to compile a complete list of components, the identification numbers of each part, material classification, suppliers, and data from Material Safety Data Sheets (MSDS) or comparable data. Manufacturers should also request from vendors information on radiation compatibility and current test data on the

INTRODUCTION The F0 algorithm was introduced several years ago in the international practice of pharmaceutical sterilization and is also officially included in the latest edition of the Italian Pharmacopoeia. Yet F0 is still scarcely used and sometimes is even regarded with some suspicion from a conceptual point of view. On the contrary, F0 is extremely useful for adjusting, controlling and validating moist-heat sterilization processes. The purpose of this technical note is to clarify the nature of F0 and of related parameters (D, z, PNSU), and to explain their use for the setting, adjustment, control and validation of moist-heat sterilization processes. THE AUTHORS CONTENTS 1. ESSENTIALS OF STEAM STERILIZATION KINETICS 1.1 D-VALUE OR DECIMAL DECAY TIME 1.2 STERILITY AS "PROBABLE EFFECT" OF EXPOSURE TIME 1.3 Z-VALUE OR TEMPERATURE COEFFICIENT 1.4 F0 OR EQUIVALENT EXPOSURE TIME AT 121°C 1.5 LETHALITY RATES OR LETHALITY FACTORS 1.6 EXAMPLE OF POST-CALCULATION OF F0 1.7 SYMBOLS AND DEFINITIONS USED IN STERILIZATION TECHNOLOGY 2. DEFINITION OF "STERILE" AND "STERILIZATION" 3. REAL TIME CALCULATION OF F0 WITH A COMPUTERIZED AUTOCLAVE 3.1 "TRADITIONAL" CONTROL BASED ON EXPOSURE TIME 3.2 F0-BASED CONTROL 3.3 STERILIZATION TIME-BASED CONTROL WITH CALCULATION/PRINTOUT OF VALUES 4. SUMMARY OF PRECEDING CONCEPTS IN LAYMAN'S TERMS 5. BIBLIOGRAPHY 5.1 LITERATURE CITED 5.2 SIGNIFICANT REFERENCE

F0

1. ESSENTIALS OF STEAM STERILIZATION KINETICS Let us suppose to immerse in pressurized saturated steam, at constant temperature ,a system contaminated by a micro biological species (which we assume, for the sake of simplicity, to be pure and homogeneous): e.g. a vial containing an aqueous suspension of a certain sporogenous micro-organism. It has been experimentally shown that, under the above conditions, the reaction of thermal degradation of the micro-organism at issue obeys the laws of chemical reactions. Using N to indicate the number of

micro-organism present in the system at a given moment, the variation of this number as the function of a chosen time t of exposure to the selected sterilization temperature can be written as:

where K is a constant which is typical of the species and conditions of the chosen microorganism. The degradation reaction, i.e. the sterilization reaction, therefore develops like a first order chemical reaction (i.e. like a chemical decomposition reaction) in which the reaction rate is proportional, in each moment, only to the amount of product still to be degraded (or decomposed). This seems to be obvious for dry sterilization, but less rigorous for steam sterilization, in which the water vapour molecules also seem to take part in the reaction. Actually, this bimolecular reaction is of the first order, since the steam is present in high excess all the reaction long and its concentration may be regarded as constant. The above expression can be developed as follows:

and, by converting to base 10 logarithms (from base e or Naperian logarithms, which are less practical in this specific case), the following is obtained: log N = - kt + constant where k=K/2.303 due to the shift from basee logarithms to base 10 ones. At time zero, the following is true: therefore t=0 N = N0 from which log N0 = - kt + log N0 which leads to

and therefore

Where: N0 = initial number of micro-organism t = elapsed exposure (= sterilization) time N = number of micro-organism after the exposure time t k = reaction rate constant which depends on the species and conditions of the microorganism Expression (3) shows that the number of micro-organism decreases exponentially depending on the sterilization time. If this expression is converted into a chart, with log N as the function of t, Diagram 1 is obtained:

Diagram 1 Here we see that a constant percentage reduction of the concentration of viable microorganism occurs for each arbitrary time interval t. We can therefore draw a first conclusion: The time required to reduce the micro-organism concentration to any pre-set value is the function of its initial concentration. The sterilization reaction is therefore neither an "all-or-nothing" process nor a "potential barrier" process as was once thought. 1.1 D-VALUE OR DECIMAL DECAY TIME The D-value is defined as the decimal (or decadal) decay (or reduction) time: i.e. it is the time required, at a specified temperature T, to reduce the microbial population being considered by one logarithmic value, i.e. from 100% to 10% of the initial value. It is very easy to calculate the D-value on the base of the above expression (3): it is the reciprocal of the reaction rate k, since if t = k -1, it is N = 0.1N0. At the temperature of 121°C, the D-values generally oscillate between 0.2 and 2 minutes: very often D121 = 1 is assumed in the absence of more specific experimental data. It is immediately evident that the result of sterilization at constant temperature can be very different depending on the D-value of the contaminating microbial species (or on the largest D-value, in case of mixed contamination). The following graph shows that a residual contamination of 10 -6 is achieved in eight minutes, starting from an initial unit contamination of 102, at 121°C if D = 1. Sixteen minutes are required for the same result if D = 2 and 4 are sufficient if D = 0.5 (see Diagram 2).

Diagram 2 1.2 STERILITY AS "PROBABLE EFFECT" OF EXPOSURE TIME Let us now consider what happens within a batch of units (vials, bottles or others) with an initial constant unit contamination of 100 micro-organisms = 102. If the D-value at 121°C is assumed = 1, after one minute at 121°C, the reduction = to 101 = 10 micro-organisms is achieved; after another minute, only 100 = 1 micro-organism is still surviving. After another minute the surviving microbial population would be 10-1 = 1/10 micro-organism. A contamination of 1/10 must not be understood to mean that each unit contains 1/10 of a micro-organism, which is biologically meaningless (in this case the unit would probably be sterile...) but that there is a probability of having 1/10 of the units still contaminated within the batch of sterilized units. In fact, three minutes would be the necessary time to reduce the microbial population to a single surviving micro-organism if the initial population were ten times larger than the one at issue. This higher initial contamination could be regarded either as a ten times larger number of micro-organism in the same unit, or as the initial contamination of a ten times larger unit. If the unit is not considered any longer as the single vial or bottle, but as the whole of all the items produced over a period of time, the initial number of micro-organism present in each item has to be multiplied times the number of items produced, and the exposure time to achieve the reduction to the same number of viable micro-organism left in the whole of the items produced, has to be correspondingly increased. The following example will be helpful to focus the matter. A new sterile product in ampoules has to be launched; the number of ampoules to be produced over all the life period of the product is expected to be 1010. The maximum number of contaminated ampoule deemed to be acceptable is 100 = 1: this obviously means that the probability of having non sterile ampoules after the sterilization must not exceed 10-10. Let us also suppose that the microbial population within each ampoule after the filling and the sealing does not exceed 103 micro-organisms: these must be destroyed by mean of moist heat terminal sterilization at 121°C. The applicable D-value is 1 minute. The total number of micro-organism to be destroyed during the life of the product will be: 1010+3 = 1013 If this whole microbial population were exposed to moist heat at 121°C over a period of thirteen minutes, it would be reduced to 10-13 times it initial number, i.e. to 1013-13 = 100 = 1. The exposure time of thirteen minutes would thus be sufficient (under all the other above hypotheses) to prevent the total number of contaminated ampoules from exceeding the value of one. From the point of view of each single ampoules, thirteen minutes of exposure would reduce the microbial population to the theoretical value of :

103-13 = 10-10 To interpret this numeric value as the probability of still having one contaminated ampoule in ten thousand million sterilized ampoules means that a single ampoule will still be contaminated out of a whole of 1010 (or ten ampoules out of a whole of 1011). This probability value is defined as PNSU (Probability of Non Sterile Unit). In recent times the PNSU as sterility evaluation criterion is being replaced by the SAL (Sterility Assurance Level). The name itself could generate some misunderstanding since a level of assurance is commonly deemed to be good if high, but SAL seems to have beendefined in such a way that its numerical value is the same of PNSU. This notwithstanding, it is sometimes calculated as the reciprocal value of PNSU. The SAP (Sterility Assurance Probability) criterion has been proposed as well: SAP seems for the moment to have been granted the same definition of PNSU, even if it would be better understandable if its value approached the unity after a satisfactory sterilization. The above discussion and example lead to the conclusion that the optimum exposure time of a sterilization process must take in due account not only the initial microbial population within the single item to be sterilized and the species and conditions of the contaminating micro-organism, but also the total number of items expected to be sterilized over the life period of the product. The survival lines so far examined are strictly theoretical. Actually, the lines are not straight and the most common difference is that they are concave or convex, especially for high concentrations: i.e. they resemble the path of curves B and C with respect to the theoretical straight-line path A (see Diagram 3).

Diagram 3 1.3 Z-VALUE OR TEMPERATURE COEFFICIENT All the above considerations have been developed under the basic assumption that the temperature is kept constant all the exposure time long. It seems rather obvious that the D-value will change as the temperature changes. If the D-values experimentally obtained for a given microbial species are plotted on a semilogarithmic chart as the function of the temperature T, a path similar to Diagram 4 is obtained:

Diagram 4 In this case, it can be seen that D-value is 1 minute at 121°C (i.e. the average value which is very often assumed to be acceptable in the absence of more exact experimental data). It can also be seen that D-value varies by a factor of 10 if the temperature varies by 10°C. The z-value is defined as the temperature coefficient of microbial destruction, i.e. as the number of degrees of temperature which causes a 10-fold variation of D (or, more generally, of the sterilization rate). The z-values generally oscillate between 6 and 13 for steam sterilization in the range 100 to 130°C; zvalue is often assumed to be equal to 10 in the absence of more precise experimental data. The fact that D-value varies by 10 times for a variation of 10°C when z = 10 must not lead to the false assumption that D varies by one time (i.e. doubles) for an increase of 1°C; obviously this is not true. It is actually a matter of finding the number which yields 10 when raised to the tenth power. This number is 1.24. Therefore a variation of 1°C entails a variation of D-value of 24%. As can be seen, this is quite a considerable value which illustrate the dramatic effects which are generated when the sterilization temperature is also only a few degrees lower than the expected value, perhaps only in some point of the load. It is also useful to remember that the effect of temperature variation decreases considerably as the temperature raises and drops to approximately one half (and even less) for dry sterilization at approximately 200°C. Under these condition z-value is about 20 instead of about 10. Therefore, the small temperature differences which can be so dramatic in steam sterilization are much less effective in dry sterilization. Table 1 lists "average" D-values and z-values for some "typical" micro-organism; in fact the actual Dvalues and z-values depend to a large extent on the medium which contains the micro-organisms and on their history. AVERAGE VALUE OF D AND z FOR SOME TYPICAL MICRO-ORGANISMS Micro-organism Clostridium botulinum Bacillus stearothermophilus D121 (minutes) 0.2 2.0 z (°C) 10 6

Bacillus subtilis Bacillus megaterium Bacillus cereus Clostridium sporogenes Clostridium histolyticum Table 1

0.5 0.04 0.007 0.8 - 1.4 0.01

10 7 10 13 10

Actually, at 121°C no micro-organism has exactly D = 1 and z = 10. However, the combined use of these two parameters in calculating F0 and PNSU provides ample margins of safety as regards the microorganisms which are commonly dealt with. 1.4 F0 OR EQUIVALENT EXPOSURE TIME AT 121°C As seen above, D is thus a different function of the exposure temperature T for each different micro-organism: D = D(T) On the basis of the definition of coefficient z it has also to be: D ( T- z ) = D ( T )*10 With the obvious condition that D = D0 if T = T0, the mathematical function which satisfies the above relationship is (see further explanation in the note at the end of this paragraph):

where D0 is the value of D at the temperature T0 and for a given micro-organism. The basic assumption which leads to the above formula is obviously that the z-value is the same on both sides of the reference temperature T0. No doubt this is rigorously not true, but it has proven to be both a helpful and a safe abstraction. Let us now calculate the time interval required to obtain at a constant temperature T0 the same reduction of a microbial population obtained at the actual exposure temperature T, continuously variable over a certain time interval t. It has obviously to be:

and recalling expression (1) and the definition of D-value:

D-value is variable with the actual exposure temperature and is given by expression (4), but D0 is a constant, so we may write:

It is thus possible to calculate the lethal effect of the exposure of a microbial population to a variable temperature T by relating it to an hypothetical sterilization performed at a constant temperature T0 for the time t0. If the constant reference temperature is assumed equal to 121.11°C (originally 250°F) and the z-value equal to 10, the equivalent time given by expression (5) is named F0:

F0 is the equivalent exposure time at 121.11°C of the actual exposure time at a variable temperature, calculated for an ideal micro-organism with a temperature coefficient of destruction equal to 10. Firstly introduced by the National Canners Association in 1968 (a), F0 has to become a topic in pharmaceutical production since the FDA used it extensively in the "Proposed rules" of June 1st, 1976 (b), with the following meaning (section 212.3): "F0 means the equivalent amount of time, in minutes at 121°C or 250°F, which has been delivered to a product by the sterilization process". For the calculation of it, "a z-value of 10°C or 18°F is assumed; the term z-value means the slope of the thermal death time curve and may be expressed as the number of degrees.... required to bring about a tenfold change in the death rate". In practice, the knowledge of the temperature values as the continuous function of elapsing time is not available, and F0 is calculated as follows:

where: DELTA t = time interval between to following measurements of T T = temperature of the sterilized product at time t z = temperature coefficient, assumed to be equal to 10¡ÆC If we assume a sterilization lasting 15 minutes, constantly at 121°C, we obtain:

indeed according to the definition of F0. If we assume sterilization lasts 15 minutes, constantly at 111°C, we instead obtain:

Therefore, a 15 minutes sterilization at 111°C is equivalent, in terms of lethal effect, to 1.5 minutes at 121°C; this can be easily expected if z = 10. Similarly, if we assume a 15 minutes sterilization constantly at 124°C, we have:

1.5 LETHALITY RATES OR LETHALITY FACTORS The calculation of F0, with its exponential expression, is not immediate. Tables have therefore been developed which list the so-called Lethality Rates, i.e. the coefficients required to pass from a certain time at the temperature T to the equivalent time at 121°C, i.e. to F0. Tables 2 and 3 are two examples. The first has z = 10, and therefore allows to obtain F0 by definition. The second table has z-value variable and allows to obtain equivalent times at 121°C as before, but with values of z which can be chosen between 7 and 12. It is interesting to notice that the variation of z considerably influences the Lethality Rates when T varies. It should also be noted that when T rises the Lethality Rates rise more when z-value decreases than when it rises. This depends on the position of z-value as denominator of the fraction which is the exponent of the expression of F0. In other words, the effect of temperature variations is greater as the z-value becomes smaller. This fact will become better apparent from an inspection of the table provided in Table 3. TABLE OF LETHALITY RATES for a reference temperature of 121.11°C and z = 10°C; obtainable starting from the temperature T comprised between 90°C and 130°C with intervals of 0.1°C Temp.°C 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 +0.0 .001 .001 .001 .002 .002 .002 .003 .004 .005 .006 .008 .010 .012 .015 .019 .024 .031 .039 .049 .062 .077 .097 .123 .154 .194 .245 .308 .388 .489 +0.1 .001 .001 .001 .002 .002 .003 .003 .004 .005 .006 .008 .010 .013 .016 .020 .025 .032 .040 .050 .063 .079 .100 .126 .158 .199 .251 .315 .397 .500 +0.2 .001 .001 .001 .002 .002 .003 .003 .004 .005 .006 .008 .010 .013 .016 .020 .026 .032 .041 .051 .064 .081 .102 .128 .162 .204 .256 .323 .406 .512 +0.3 .001 .001 .001 .002 .002 .003 .003 .004 .005 .007 .008 .010 .013 .017 .021 .026 .033 .042 .052 .066 .083 .104 .131 .166 .208 .262 .330 .416 .523 +0.4 .001 .001 .001 .002 .002 .003 .003 .004 .005 .007 .008 .011 .013 .017 .021 .027 .034 .043 .054 .067 .085 .107 .135 .169 .213 .268 .338 .426 .536 +0.5 .001 .001 .001 .002 .002 .003 .003 .004 .005 .007 .009 .011 .014 .017 .022 .027 .035 .044 .055 .069 .087 .109 .138 .173 .218 .275 .346 .435 .548 +0.6 .001 .001 .001 .002 .002 .003 .004 .004 .006 .007 .009 .011 .014 .018 .022 .028 .035 .045 .056 .071 .089 .112 .141 .177 .223 .281 .354 .446 .561 +0.7 .001 .001 .001 .002 .002 .003 .004 .005 .006 .007 .009 .011 .014 .018 .023 .029 .036 .046 .057 .072 .091 .115 .144 .182 .299 .288 .362 .456 .574 +0.8 .001 .001 .001 .002 .002 .003 .004 .005 .006 .007 .009 .012 .015 .019 .023 .029 .037 .047 .059 .074 .093 .117 .148 .186 .234 .294 .371 .467 .587 +0.9 .001 .001 .002 .002 .002 .003 .004 .005 .006 .008 .010 .012 .015 .019 .024 .030 .038 .048 .060 .076 .095 .120 .151 .190 .239 .301 .379 .477 .601 LETHALITY RATE

119 120 121 122 123 124 125 126 127 128 129 130

.615 .774 .975 1.227 1.545 1.945 2.448 3.082 3.881 4.885 6.150 7.743

.629 .792 .997 1.256 1.581 1.990 2.506 3.154 3.971 4.999 6.294 7.293

.644 .811 1.021 1.285 1.618 2.037 2.564 3.228 4.063 5.116 6.440 8.108

.659 .830 1.044 1.315 1.655 2.084 2.624 3.303 4.158 5.235 6.590 8.297

.674 .849 1.069 1.346 1.694 2.133 2.685 3.380 4.255 5.357 6.744 8.490 Table 2

.690 .869 1.093 1.377 1.733 2.182 2.747 3.459 4.354 5.482 6.901 8.688

.706 .889 1.119 1.409 1.774 2.233 2.811 3.539 4.456 5.608 7.062 8.890

.723 .910 1.145 1.442 1.815 2.285 2.877 3.622 4.559 5.740 7.226 9.097

.739 .931 1.172 1.475 1.857 2.338 2.994 3.706 4.666 5.874 7.394 9.309

.757 .953 1.199 1.510 1.901 2.393 3.012 3.792 4.774 6.010 7.567 9.526

TABLE OF LETHALITY RATES for a reference temperature of 121°C and z variable between 7C° and 12°C; obtainable starting from the temperature T comprised between 100°C and 130°C with intervals of 0.5°C Temp.°C 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 114.5 115 115.5 116 116.5 117 117.5 118 118.5 119 119.5 120 120.5 7 .001 .001 .002 .003 .004 .005 .007 .010 .014 .019 .026 .037 .052 .072 .100 .118 .139 .164 .193 .228 .268 .316 .373 .439 .518 .611 .720 .848 8 .002 .003 .004 .006 .007 .010 .013 .018 .024 .032 .042 .056 .075 .100 .133 .154 .178 .205 .237 .274 .316 .365 .422 .489 .562 .649 .750 .886 9 .005 .006 .008 .010 .013 .017 .022 .028 .036 .046 .060 .077 .100 .129 .167 .190 .215 .245 .278 .316 .359 .408 .464 .527 .599 .681 .774 .880 10 .008 .010 .013 .016 .020 .025 .032 .040 .050 .063 .079 .100 .126 .158 .200 .224 .251 .282 .316 .355 .398 .447 .501 .562 .631 .708 .794 .891 11 .012 .015 .019 .023 .028 .035 .043 .053 .066 .081 .100 .123 .152 .187 .231 .257 .285 .316 .351 .390 .433 .481 .534 .593 .658 .731 .811 .901 12 .018 .022 .026 .032 .038 .046 .056 .068 .083 .100 .121 .147 .178 .215 .261 .287 .316 .348 .383 .422 .464 .511 .562 .619 .681 .750 .825 .909 LETHALITY RATE

121 121.5 122 122.5 123 123.5 124 125 126 127 128 129 130

1.00 1.11 1.39 1.64 1.93 2.28 2.68 4.39 5.18 7.20 10.0 13.9 19.3

1.00 1.16 1.33 1.54 1.78 2.05 2.37 3.16 4.22 5.62 7.50 10.0 13.3

1.00 1.14 1.29 1.47 1.67 1.90 2.15 2.78 3.59 4.64 6.00 7.74 10.0 Table 3

1.00 1.12 1.23 1.14 1.59 1.78 2.00 2.82 3.16 3.98 5.01 6.31 7.94

1.00 1.11 1.22 1.37 1.52 1.69 1.87 2.31 2.85 3.51 4.33 5.34 6.58

1.00 1.10 1.21 1.33 1.47 1.62 1.78 2.15 2.61 3.16 3.83 4.64 5.62

1.6 EXAMPLE OF POST-CALCULATION OF F0 As mentioned, it is usual for the sterilization temperature not to remain exactly at the preset value all the exposure time long; furthermore, the heating and cooling phases also entail a certain lethal dose (which has practical significance only for temperatures above 100°C) and may (but need not) be considered in calculation. The graph provided in Table 4 is an example of graphic calculation of F0 performed after the process on the basis of the recording of the sterilization temperature inside a container filled with solution. The calculation was performed by taking one minute intervals (deltat = 1), using the Lethality Rates of Table 1 and including the lethal doses of the heating and cooling phases (above 100°C). Determining F0 after the process is completed certainly is meaningful, but the real-time calculation of F0 during the process is much more interesting. This calculation is easily performed with electronic systems. In this case it is possible to control sterilization no longer in terms of sterilization time but rather in terms of F0 related to a container which has been identified, during validation, as the one which receives the smallest lethal dose of the entire load.

1.7 SYMBOLS AND DEFINITIONS USED IN STERILIZATION TECHNOLOGY Table 5 summarizes the symbols and associated descriptions of the terms most frequently used in moistheat sterilization technology.

SYMBOL DT

DIMENSION Time

DEFINITION

DESCRIPTION

D-value (Decimal The time required, at a given temperature T, to reduce decay time) the number of micro-organisms of a given species to 10% (1 logarithmic reduction) D-value at T°C The time required, at the temperature of T°C, to reduce the number of micro-organisms of a given species to 10% (1 logarithmic reduction)

D121.1°

Time

F ( z,T ) F0

Time Time

Equivalent exposure Equivalent exposure time related to the specific time temperature T and to the specific value of z indicated "Reference" exposure time, "F zero" Initial biological load Equivalent sterilization time related to the temperature of 121°C and to Z = 0 The number of viable microorganisms contained in a unit before sterilization

N0 NU

None None

Survived biological The number of microorganisms contained in a unit, load surviving a sterelization of U minutes at a given temperature z-value (Temperature coefficient) Lethal Ratio Number of degrees of temperature variation which causes a 10-fold variation in the value of D121.1° Lethaly ratio between T (The temperature being considered) and Tref. (the reference temperature, generally 121°C) for a given value of Z (generally 10)

Z

Temperature difference °C None

L

PNSU

None

Probability of Non The number which expresses the probability of Sterile Unit finding 1 non-sterile unit in a certain number of sterilized units (batch) Table 5

2. DEFINITION OF "STERILE" AND "STERILIZATION" Sterile Free from viable micro-organisms Sterilization Any physical or chemical process which destroys all life forms, with special regard to microorganisms (including bacteria and sporogenous forms), and inactivates viruses. Therefore the terms "sterile" and "sterilization", in a strictly biological sense, describe the absence or destruction of all viable micro-organisms. In other words, they are absolute terms: an object or system is either "sterile" or "non-sterile". The destruction of a microbial population subjected to a sterilization process follows a logarithmic progression. Therefore only a treatment of infinite duration provides the absolute certainty that the entire microbial population has been destroyed and that the system is sterile. Making the characteristics of the sterilization treatment more drastic (i.e. increasing time and/or temperature) usually entails a decay of the qualities of the product and certainly increases process costs. It is therefore agreed that the product is acceptable as sterile when the probability of finding a non-sterile unit in a sterilized batch entails a risk which is lower than the other risks associated with the use of the

product itself. More properly, in the pharmaceutical industry, in order to define a unit as sterile we must be able to certify, on a statistical basis related to the conditions of preparation and sterilization of that specific product and of that specific batch, that less than one unit in a million is exposed to the risk of not being sterile. The probability of finding a non-sterile unit (PNSU = Probability of Non Sterile Unit) must therefore be lower than 10-6. 3. REAL TIME CALCULATION OF F0 WITH A COMPUTERIZED AUTOCLAVE Electronic technology allows the use of a computer for the integrated management of a sterilization autoclave. If the computer is sufficiently sophisticated, besides the usual control, monitoring and alarm functions, it can also calculate F0 in real time and therefore control the process according to this algorithm. A typical computerized autoclave control system, for example, operates as follows.

Figura 1 The autoclave is generally provided with multiple heat probes in its chamber. These probes control the process: one is inserted in the sterilizer drain line, while the others are flexible and can be inserted in containers of the load to be sterilized and are immersed in the solution contained therein. The operator can choose to control the sterilization process according to three alternative modes. 3.1. "TRADITIONAL" CONTROL BASED ON EXPOSURE TIME The programmer pre-sets four parameters: 1. the sterilization temperature, e.g. 121°C 2. the acceptable oscillation of this temperature around this value, e.g. ± 0.5°C, so that the acceptable oscillation range will be 120.5°C to 121.5°C 3. the duration of the sterilization phase, e.g. 20 minutes 4. the acceptable time of excursions from the lower limit of the sterilization temperature oscillation range, e.g. 10 minutes In these conditions, the sterilization phase begins when the "coldest" heat probe, among those enabled by the programmer to control the process, has entered the acceptable range (see Figure 2). If all the oscillations of all the heat probes remain in the acceptable oscillation range, the sterilization phase end 20 minutes after the "coldest" heat probe has entered the range. However, if one or more heat probes get colder than the lower limit of acceptable oscillation, the computer reacts as follows. The duration of the "excursions" (regardless of which heat probes recorded them) are individually smaller than the parameter pre-set in step 4 (10 minutes in the example): the sterilization time count remains held

during the "exits", and therefore the duration of the sterilization phase is increased by the value of the sum of all the exits of the same probe (see Figure 3) An "excursion" is greater than the parameter set at item 4, for example 12 minutes: as soon as the excursion exceeds 10 minutes, the sterilization phase restarts from the beginning and the sterilization time count restarts only when the temperature returns within the range of tolerance. Alarms as "Sterilization temperature lack" and "Sterilization time suspended" or "Sterilization time reset" monitor the above anomalies.

3.2 F0-BASED CONTROL The programmer sets the following parameters: 1. the sterilization temperature, e.g. 121°C 2. the acceptable oscillation of this temperature around this value, e.g. ± 0.5°C, so that the acceptable oscillation range will be 120.5 to 121.5°C 3. the value of F0 which, when totalled by the coldest probe, causes the end of the sterilization phase, e.g. F0 = 15 (F0 is adjustable between 1 and 999) 4. the F0 calculation start temperature, which can be pre-set from 90°C upward: if it is set to a value 0.5°C lower than the sterilization temperature (as in Example 1, see below), only the lethal doses provided during the sterilization phase are taken into account. If it is set to 100°C (as in Example 2, see below), the lethal doses provided during heating are taken into account for terminating the sterilization phase, whereas the lethal doses provided during cooling (down to the pre-set value) are also taken into account for calculation 5. the value of the temperature coefficient z, which is variable between 5 and 20 but is normally set to 10 (to obtain a properly said F0 value). The calculation of F0 is performed independently for each probe on a very small time base: e.g. 2 seconds. Therefore, every two seconds and for every probe, the computer takes the temperature of entry and exit from the time base, averages them, inputs this average temperature into the formula of F0, calculates partial F0 and adds it to the previously accumulated F0 for that probe. Every 20 seconds (or a longer or shorter interval, depending on programming) these values are recorded by the printer of the computer in digital terms. The values accumulated by the coldest and hottest probes are displayed on the screen and are refreshed every 2 seconds. When they reach the pre-set value, the sterilization phase ends. Let us examine some examples of F0-based control which will clarify the above description. For the sake of simplicity they refer to a single probe.

Example 1 (Figure 4) The calculation of F0 starts when the sterilization begins, i.e. when the calculation start temperature corresponds to the lower temperature of the acceptable oscillation range. The phase ends when the probe (assumed to be the least favoured) has accumulated the preset value of F0 (12 in this case). The calculation of F0 ends when the sterilization phase terminates. Example 2 (Figure 5) The calculation of F0 starts when the probe exceeds the pre-set value (100°C in this case) during the heating phase. When the sterilization phase is entered, the probe has already accumulated an F0 of 1.1 minutes. The sterilization phase ends when the probe has accumulated the pre-set F0 value (15 in this case). However, the calculation of F0 continues until the probe leaves the pre-set value of 100°C. It can thus be seen that an additional lethal dose F0 = 0.9 minutes is provided during the cooling phase.

The calculation of the lethal doses provided during heating and cooling is necessary when highly heatsensitive products are sterilized. The ability to select the value of z allows the calculation of lethal doses with respect to the heat-sensitivity characteristics of a specific and critical contaminating micro-organism. This possibility must be considered as a refinement in calculation allowed by the capabilities of the computer. Obviously, when a process is controlled according to F0, "excursions" from the acceptable temperature oscillation range no longer cause the reactions specified in items a) and b) of paragraph 3.1. Actually, if the temperature drops, the lethal dose accumulated during that period is automatically reduced in the calculation of F0. The reverse is true if the temperature rises. However "excursions" from the acceptable temperature range (whether above or below it) still generate the alarm "Sterilization temperature lack" as in the case of paragraph 3.1, whereas suspension or reset of sterilization time are no longer applicable. The F0-based management of the sterilization process allows highly rational control of the procedure even in case of power loss or blackout. In such conditions, the computer, which is battery buffered, continues to operate but naturally no longer receives signal from the autoclave; the autoclave itself is equally unable to execute the command signals sent by the computer. In case of power failure, all the autoclaves valves and blocking devices are naturally moved to their resting position, which corresponds to the maximum safety condition. Example 3 (Figure 6) Assume now the power failure occurs during the sterilization. The computer is capable of detecting the times at which the power failure starts and ends, and the temperature at which each heat probe enters and exits the power failure period. In practice, the conditions of Figure 6 occur; as in the previous examples, Figure 6 relates to a single probe for the sake of simplicity.

The computer has naturally been unable to determine the trend of the temperature during the time interval Ts-Te. When power returns, it therefore calculates F0 for this time interval on the basis of the linear interpolation between the temperatures Ts-Te. Such calculation is conservative with respect to the actual trend of the temperature (indicated in broken lines). Even if not immediately intuitive, the shape of the actual trend can easily be demonstrated with experimental investigations. Example 4 (Figure 7) If the power failure has lasted a long enough as to entail the exit of the temperature from the F0 calculation start value (e.g. 100°C), the reaction of the computer when the power failure ends is schematically indicated in Figure 7 and can be summarized as follows: linear interpolation between Ts and Te; calculation of F0 during power failure as linear interpolation between the temperatures Ts-100°C for the

time interval t1-t100; at the end of the blackout, the regular calculation of F0 resumes only when the temperature again exceeds 100°C. Obviously, F0-based control of sterilization is extremely useful in all sterilization processes. It is practically indispensable when it is necessary to sterilize highly heat-sensitive products for which the "survival probability" approach has been adopted during validation. The heat probes enabled for calculation must naturally be inserted in the solution of a few representative units arranged in the point (or, more realistically, in the region) of the load which has been determined as "coldest" during validation.

3.3. STERILIZATION TIME-BASED CONTROL WITH CALCULATION/PRINTOUT OF F0 VALUES Sterilization is controlled exactly as specified in paragraph 3.1. However, the programmer also pre-sets the parameters of items 6 and 7 of paragraph 3.2. This phase is therefore ended when an "effective" sterilization time is reached, but the calculation of F0 is simultaneously performed and printed (for each enabled probe) as specified in paragraph 3.2. This calculation is merely for verification, but is nonetheless important, since it allows the determination of lethal doses provided in the points monitored by the enabled heat probes. The calculation is extremely useful when the sterilization process is validated with the "overkill" (i.e. "superabundant lethal dose") approach, in which, as it known, it is necessary to prove that a lethal dose equal to at least F0 = 12 has been provided during the sterilization phase to the coldest point of the load. It is evident that if a couple of flexible probes enabled for F0 calculation (and appropriately set for this purpose) are introduced in representative containers arranged in the coldest points of the load, they will provide F0 values which can be accepted as unequivocal evidence of the execution of sterilization in the spirit of the previously performed validation. 4. SUMMARY OF PRECEDING CONCEPTS IN LAYMAN'S TERMS The following simplified summary may be used to explain these concepts in an easily understood manner to those who may be less trained, but who would nevertheless benefit from grasping the essence of the work they are performing. NOTE: the term "Unit" defines a physically delimited system within which micro-organism can "homogenate" and proliferate. A bottle or vial, together with their contents, are a unit. It is more difficult but equally necessary to extend the concept of unit to a container which contains for example a filtering system or a certain mass of clothing.

1. Up to just a few years ago, steam sterilization was thought to be a "potential-barrier", i.e. "all-ornothing", phenomenon. This would mean that once a certain temperature is reached and maintained for a certain time, all the micro-organisms contained in a unit die within that time, regardless of their number. The risks of such an assumption are evident. 2. Nowadays, it has been shown that steam sterilization instead proceeds like a first order chemical reaction and therefore at a specific rate which is higher as the temperature rises and is a function of the number of micro-organisms present in the unit. 3. This rate can be expressed by means of the Decimal Decay Time, indicated by the D-value. 4. The D-value is the time, in minutes, required to reduce the number of microorganisms present in the unit by 90%. 5. The D-value varies according to the kind of micro-organism (and to its "history"), the medium in which it is immersed and, as mentioned, the sterilization temperature. 6. At the temperature of 121°C, the D-value is generally between 0.5 and 2 minutes: for microorganisms commonly dealt with we can assume, as an average, that D = 1 minute. 7. This means that at the end of each minute at 121°C the number of micro-organisms reduces to one tenth of the number at the beginning of that minute. 8. Therefore, if a unit is kept at 121°C for 3 minutes, the number of micro-organisms contained therein is reduced to one thousandth (1/10 x 1/10 x 1/10 = 1/1000) of the initial number. 9. If the initial bacterial load of a batch of units being sterilized is on the average 1000 (i.e. 1000 micro-organisms per vial or bottle), after 3 minutes of treatment at 121°C it is reduced on the average to 1. 10. After a further minute of sterilization (4 minutes altogether) this reasoning leads one to the conclusion that the load has dropped to 1/10, i.e. 0.1. However, this must not be understood to mean that at this point each unit contains one tenth of a microorganism (in which case the units would be sterile...) but must be taken to mean that there is a probability that 1/10 of the units are still contaminated. 11. After 9 minutes of treatment at 121°C, the bacterial load of the batch at issue is reduced, on the average, to 1/1,000,000. The probability of still having a contaminated unit in that batch is therefore 1 in 1,000,000. 12. This is the minimum assurance of sterilization which must be achieved in the pharmaceutical field, though a greater assurance, for example 10 9 - , i.e. 1 in 1 billion, is often sought. 13. This assurance is expressed as PNSU: Probability of Non Sterile Unit. PNSU =10-6 means that the probability of finding a non-sterile unit in a batch is 1 in 1 million. 14. In order to achieve a given PNSU it is necessary to meet several conditions: • to statistically know the initial bacterial load of the batch (which is anything but easy to determine) • to be certain that even the coldest point inside the units of the batch has received a lethal heat dose sufficient to obtain the required PNSU • if the sterilization at 121°C is not performed, to be capable of relating to 121°C (by calculation) the effectiveness of sterilization in order to correctly apply the previously defined concept of D 15. F0 is defined as: • the time during which sterilization is actually performed at 121°C, or • the time during which sterilization is performed at another sterilization temperature, related by calculation to 121°C so as to be equivalent in terms of lethal heat dose, i.e. of microbial destruction effectiveness NOTE: The exact reference temperature of F0 is 121.11 °C, as this value corresponds to 250 °F 16. The "overkill", i.e. "over-sterilization", approach is generally used when a sterilization process for heat-resistant products is validated. Essentially, with this approach it is necessary to provide an F0 which is safety and routinely not lower than 12 (and indeed has a good safety margin with respect to this minimum value) exclusively during the sterilization phase (i.e. ignoring the lethal heat doses provided during heating and cooling) to the unit placed in the coldest point of the load.

17. In practice, it is conceptually easy and relatively trouble-free to relate by calculation the sterilization time to 121°C or to F0 after the process. On the contrary, this is difficult to do in "real time", i.e. while sterilization is in progress, since the calculation must be performed so quickly that the use of a computer is unavoidable. 18. If F0 = 12 is to be achieved, the required exposure time is less than 12 minutes if the sterilization temperature is greater than 121°C and greater than 12 minutes if the sterilization temperature is lower than 121°C. 19. Let us now try to quantify that "less" and "greater" than 12 minutes. For most of the microorganisms with which we commonly deal, it is assumed that every 10°C of shift from the temperature of 121°C entail a tenfold change in the sterilization rate. 20. Therefore, if we work at 111°C, in order to achieve an F0 equal to 12 it is necessary to sterilize for 12 x 10 = 120 minutes, whereas if we work at 131°C then 12/10 = 1.2 minutes, i.e. 72 seconds, are sufficient. 21. If we want to determine the extent by which the sterilization rate varies for temperature variations of 1°C we must find the number which yields 10 when raised to the tenth power: this number is 1.24. This means that a 1°C variation in the sterilization temperature causes an increase (or reduction) of the sterilization rate by a factor of 1.24, i.e. 24%. 22. Similarly, it can be shown that a temperature variation of 0.1°C causes a rate variation with a ratio of 1÷1.02, i.e. approximately 2%. 23. It is therefore evident that even small temperature variations around 121°C cause highly significant and hardly negligible variations in the sterilization rate. For example, sterilizing at 119°C in fact means increasing (approximately) the exposure time by 1.24 x 1.24 = 1.5376 times to relate it to 121°C. Therefore, for example, if F0 = 12 is to be achieved, it is necessary to sterilize for about 19' instead of 12'. 24. The following mathematical expression allows the calculation of F0 and is provided for information:

where T is the actual temperature at the time being considered, and the number at the denominator of the exponent is the number of degrees C which causes a 10-fold variation of the sterilization rate (z-coefficient). 25. A Lethality Rate table (see Table 6) has been compiled which allows to pass, by means of a simple multiplication, from any sterilization time at a certain temperature at a certain temperature to F0 for temperatures between 90 and 130.9°C with intervals of 0.1°C. 26. Let us analyse Table 6. Choose the temperature, in whole Centigrade degrees, in the left column and the tenths of degree to be added in the top row. The intersection of the two values yields the required Rate. For example, the Rate framed with thin lines is for 120.0 °C, the double framed Rate is for 120.2°C and the thick-framed Rate is for 121.8°C. The Rate for 121.1°C is naturally approximated to 1 (it would be exactly 1 for 121.11°C). 27. Therefore, if we refer to the factor for 120.0°C we can say that any sterilization time at 120.0°C must be multiplied by 0.774 to make it equal to the time at 121.1°C, i.e. to express it as F0. Therefore: 1 minute at 120.0°C = 1' x 0.774 = 0.77 minutes at 121.1°C 15 minutes at 120.0° = 15' x 0.774 = 11.61 minutes at 121.1°C 20 minutes at 120.0°C = 20' x 0.774 = 15.87 minutes at 121.1°C NOTE: The decimals of the time values are tenths and hundredths of a minute, not seconds.

28. If a calculation of F0 after the process is to be performed on the basis of a chart of the temperature taken inside a unit subjected to sterilization, it is possible to operate as described in Table 4 (paragraph 1.6.) 29. Figure 8 is an illustration of the concepts of F0, D and PNSU. TABLE OF LETHALITY RATES for a reference temperature of 121.11°C and z = 10°C; obtainable starting from the temperature T comprised between 90°C and 130°C with intervals of 0.1°C Temp.°C 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 +0.0 .001 .001 .001 .002 .002 .002 .003 .004 .005 .006 .008 .010 .012 .015 .019 .024 .031 .039 .049 .062 .077 .097 .123 .154 .194 .245 .308 .388 .489 .615 .774 .975 1.227 1.545 1.945 2.448 3.082 3.881 4.885 6.150 7.743 +0.1 .001 .001 .001 .002 .002 .003 .003 .004 .005 .006 .008 .010 .013 .016 .020 .025 .032 .040 .050 .063 .079 .100 .126 .158 .199 .251 .315 .397 .500 .629 .792 .997 1.256 1.581 1.990 2.506 3.154 3.971 4.999 6.294 7.293 +0.2 .001 .001 .001 .002 .002 .003 .003 .004 .005 .006 .008 .010 .013 .016 .020 .026 .032 .041 .051 .064 .081 .102 .128 .162 .204 .256 .323 .406 .512 .644 .811 1.021 1.285 1.618 2.037 2.564 3.228 4.063 5.116 6.440 8.108 +0.3 .001 .001 .001 .002 .002 .003 .003 .004 .005 .007 .008 .010 .013 .017 .021 .026 .033 .042 .052 .066 .083 .104 .131 .166 .208 .262 .330 .416 .523 .659 .830 1.044 1.315 1.655 2.084 2.624 3.303 4.158 5.235 6.590 8.297 +0.4 .001 .001 .001 .002 .002 .003 .003 .004 .005 .007 .008 .011 .013 .017 .021 .027 .034 .043 .054 .067 .085 .107 .135 .169 .213 .268 .338 .426 .536 .674 .849 1.069 1.346 1.694 2.133 2.685 3.380 4.255 5.357 6.744 8.490 +0.5 .001 .001 .001 .002 .002 .003 .003 .004 .005 .007 .009 .011 .014 .017 .022 .027 .035 .044 .055 .069 .087 .109 .138 .173 .218 .275 .346 .435 .548 .690 .869 1.093 1.377 1.733 2.182 2.747 3.459 4.354 5.482 6.901 8.688 +0.6 .001 .001 .001 .002 .002 .003 .004 .004 .006 .007 .009 .011 .014 .018 .022 .028 .035 .045 .056 .071 .089 .112 .141 .177 .223 .281 .354 .446 .561 .706 .889 1.119 1.409 1.774 2.233 2.811 3.539 4.456 5.608 7.062 8.890 +0.7 .001 .001 .001 .002 .002 .003 .004 .005 .006 .007 .009 .011 .014 .018 .023 .029 .036 .046 .057 .072 .091 .115 .144 .182 .299 .288 .362 .456 .574 .723 .910 1.145 1.442 1.815 2.285 2.877 3.622 4.559 5.740 7.226 9.097 +0.8 .001 .001 .001 .002 .002 .003 .004 .005 .006 .007 .009 .012 .015 .019 .023 .029 .037 .047 .059 .074 .093 .117 .148 .186 .234 .294 .371 .467 .587 .739 .931 1.172 1.475 1.857 2.338 2.994 3.706 4.666 5.874 7.394 9.309 +0.9 .001 .001 .002 .002 .002 .003 .004 .005 .006 .008 .010 .012 .015 .019 .024 .030 .038 .048 .060 .076 .095 .120 .151 .190 .239 .301 .379 .477 .601 .757 .953 1.199 1.510 1.901 2.393 3.012 3.792 4.774 6.010 7.567 9.526 LETHALITY RATE

Table 6

5. BIBLIOGRAPHY 5.1 LITERATURE CITED (a) National Canners Association, "Laboratory Manual for Food Canners and Processors", Vol. 1, AVI Publishing Co., Westport, CT, 1968. (b) F. D. A., "Current Good Manufacturing Practice in Manufacture, Packing or Holding of LVPs", Proposed Rules for 21 CFR Part 212, Federal Register, Vol. 41, No. 106, June 1, 1976. 5.2 SIGNIFICANT REFERENCES Stumbo, C. R., Thermobacteriology in Food Processing, Academic Press, 19732. "Validation of Steam Sterilization Cycles", Technical Monograph No. 1, Parenteral Drug Association, Philadelphia, PA, 1978. Akers, M. J., "Dynamics of microbial growth and death in parenteral products", Journal of Parenteral Drug Association, 33 372 (1979). Pflug, I. J., Textbook for an Introductoty Course in the Microbiology and Engineering of Sterilization Processes, University of Minnesota, 19825. United States Pharmacopeia, XXI, 1985, p. 1351. "Guideline for Industrial Moist Heat Sterilization of Medical Products", American National

Standard, Association for the Advancement of Medical Instrumentation, Arlington, VA, 1987

Equipment qualification
9.1 Prior to the commencement of any Process Validation studies it is necessary to demonstrate and certify that the F-F-S Machine and any supporting/subsidiary equipment, sub-systems and services are properly installed and functioning in accordance with their basic design parameters. 9.2 For new equipment, qualification begins with the establishment of design, purchase and installation requirements. 9.2.1 These requirements should be specified in writing and should include those matters relevant to the F-F-S machine itself, in addition to design specifications for ancillary equipment, where relevant. 9.2.2 These design and installation requirements must be specific to the type and model of the equipment required. 9.3 Installation Qualification of new equipment should be based on written procedures and the results documented. 9.3.1 These written procedures should ensure that the pre-defined construction and installation requirements are confirmed as being met, during the actual installation process. 9.3.2 All key installation parameters should be recorded, and certified as conforming to the pre-determined requirements prior to operational qualification of the equipment. 9.4 For existing equipment, installation qualification may consist of defining existing equipment design and installation parameters from records and from direct assessment. 9.4.1 This equipment should then be evaluated for its ability to meet the defined process specifications and for the determination of any mechanical upgrading or procedural modifications needed to meet process requirements. 9.4.2 Any modification should be documented as having been performed in accordance with predetermined requirements, and certified as rendering the equipment suitable for Process Validation Studies. 9.5 The Installation Qualification phase should be designed to ensure that the specified construction and installation requirements are met, including correct provision of, and connection to, all services, power-supplies, drainage systems and all ancillary equipment and instruments. In addition it should also cover all basic functional checks, including: 9.5.1 Operation of all electric motors, pumps etc. (e.g. extruder drive motor, hydraulic vacuum pumps). 9.5.2 Operation of all automatic valves, switches etc. 9.5.3 Operation of automatic systems for each of the pre-defined stages of production. This includes all computerized process control systems associated with the operation of the machine. 9.5.4 Operation of steam traps. 9.5.5 Operation of extruder heaters. 9.5.6 Operation and designation of thermocouples. 9.5.7 Setting and operation of alarm systems. (e.g. Air shower filter blockage, filter damaged switches). 9.5.8 Operation of hydraulic system. (e.g. Mould carriage, mould closing systems). 9.5.9 Positioning of main and head moulds (in relation to each other and to the platen). 9.5.10 Operation of the extruder including position of die and pin.

9.5.11 Fixing of timer settings for each stage of the process. 9.6 Operational Qualification consists of checking the equipment (as installed) over its defined operating range in order to verify that it will perform consistently with the pre-determined limits. 9.6.1 Three or more test-runs should be performed in order to demonstrate through documented, certified evidence that:

• • •

operational parameters are maintained as pre-set for each test-run; all controls, alarms, indicators, and sensing, monitoring and recording devices function correctly; written procedures accurately reflect equipment operation.

9.6.2 Functions requiring attention in the specific context of F-F-S technology include:

• • • • • • •

the equipment/pipe-line sterilization process (including steam supply temperature and pressure, temperature mapping for "cold point" determinations; the overall profile of the sterilization cycle should be monitored in order to minimize the use of excessive heating and/or time at elevated temperature to bring the coldest part to the required temperature); fluid and air flows, including mould coolant temperature and flow-rate and air supply pressure for each function; timer settings for each stage of the process; flushing and cleaning of all product and other fluid pathways (in respect of each product manufactured); the filter drying process; extrusion of polymer and formation of product units to the required specification (e.g. appearance, size, shape, wall thickness, fill volume, opening characteristics etc.; conformance to the specifications should be assessed for each change in variable such as mould shape and size, type of polymer, product formulation, product filter etc.); filter testing - to cover the testing of all filters, and to include the establishment of filter test frequency for routine production.

9.7 Equipment must be certified as operationally qualified before any subsequent studies can be considered valid.

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Gamma Radiation Sterilization: Effects on Medical Devices
ABSTRACT This paper will highlight the need for selecting appropriate plastic polymers for medical devices. Today, gamma radiation processing is one of the most important means for the terminal sterilization of these products. the physical changes which occur within the various resins after receiving a sterilizing dose are well documented. However, the other contributing causes of part failures are less well known. INTRODUCTION The trend toward the use of gamma radiation as the method of choice for the sterilization of medical devices has increased the knowledge of the mechanisms of action of radiation on various resins. This trend has sped up the process of developing new resins and blends which will withstand gamma radiation creating more options for the medical device manufacturer today than ever before. However, the selection of a plastic resin for a medical device has largely been a matter of intended use of the product, design constraints and material costs with the method of sterilization added as an ‘afterthought’. PRESENT CONCERNS This paper addresses the concerns of the medical device industry regarding the gamma irradiation process. Concerns such as how to begin an investigation into the use of gamma radiation process; how to select the right materials; what tests to perform; how to integrate national and international regulations for the process; GMP requirements; the need to design for more than one sterilization technology; embrittlement; discoloration; material costs and availability; interaction with drug components. Our intent, is to assist you, the medical device manufacturer to obtain the greatest benefit from the use of gamma radiation sterilization; to direct your efforts along the most productive routes; to provide appropriate information; to help you avoid ‘re-inventing the wheel’ and; to facilitate the gathering of appropriate data for regulatory approval. To that end the reader is urged to refer to the review articles listed in the reference section (1,2,3,4). WHAT IS GAMMA RADIATION PROCESSING? Gamma radiation processing can be defined as the controlled exposure of a product to ionizing radiation. This controlled exposure must ensure that the specified dose of radiation is delivered to the product. The specified dose is that which will reduce the bioburden to the desired level without damaging the product. It encompasses both the

minimum and maximum dose of radiation. The minimum dose (Dmin ) ensures the proper microbiological reduction, while the maximum process dose (Dmax) ensures that the functional specifications of the product are met. By controlling the time spent in the irradiation chamber, and the manner in which the product is loaded in the product transfer device, the radiation dose received by the product is kept within these limits. Gamma radiation processing involves the deposition of ionizing energy. Radiant energy is deposited within the molecules of resin causing changes in the molecular structure and the formation of free radicals. As the energy is dissipated, there is some heating of the product. Further information on the physical characteristics of ionizing radiation can be found in reference 5. A successful gamma radiation process encompasses three basic elements (6). They are Product Qualification, Equipment Qualification and Process Qualification. All three combine to provide a validated process. While the primary focus of this paper is on Product Qualification, Process Qualification will also be discussed.

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Gamma Radiation Sterilization: Effects on Medical Devices
ABSTRACT This paper will highlight the need for selecting appropriate plastic polymers for medical devices. Today, gamma radiation processing is one of the most important means for the terminal sterilization of these products. the physical changes which occur within the various resins after receiving a sterilizing dose are well documented. However, the other contributing causes of part failures are less well known. INTRODUCTION The trend toward the use of gamma radiation as the method of choice for the sterilization of medical devices has increased the knowledge of the mechanisms of action of radiation on various resins. This trend has sped up the process of developing new resins and blends which will withstand gamma radiation creating more options for the medical device manufacturer today than ever before. However, the selection of a plastic resin for a medical device has largely been a matter of intended use of the product, design constraints and material costs with the method of sterilization added as an ‘afterthought’. PRESENT CONCERNS This paper addresses the concerns of the medical device industry regarding the gamma irradiation process. Concerns such as how to begin an investigation into the use of gamma radiation process; how to select the right materials; what tests to perform; how to integrate national and international regulations for the process; GMP requirements; the need to design for more than one sterilization technology; embrittlement; discoloration; material costs and availability; interaction with drug components. Our intent, is to assist you, the medical device manufacturer to obtain the greatest benefit from the use of gamma radiation sterilization; to direct your efforts along the most productive routes; to provide appropriate information; to help you avoid ‘re-inventing the wheel’ and; to facilitate the gathering of appropriate data for regulatory approval. To that end the reader is urged to refer to the review articles listed in the reference section (1,2,3,4). WHAT IS GAMMA RADIATION PROCESSING? Gamma radiation processing can be defined as the controlled exposure of a product to ionizing radiation. This controlled exposure must ensure that the specified dose of radiation is delivered to the product. The specified dose is that which will reduce the bioburden to the desired level without damaging the product. It encompasses both the minimum and maximum dose of radiation. The minimum dose (Dmin ) ensures the proper microbiological reduction, while the maximum process dose (Dmax) ensures that the functional specifications of the product are met. By controlling the time spent in the irradiation chamber, and the manner in which the product is loaded in the product transfer device, the radiation dose received by the product is kept within these limits. Gamma radiation processing involves the deposition of ionizing energy. Radiant energy is deposited within the molecules of resin causing changes in the molecular structure and the formation of free radicals. As the energy is dissipated, there is some heating of the product. Further information on the physical characteristics of ionizing radiation can be found in reference 5. A successful gamma radiation process encompasses three basic elements (6). They are Product Qualification, Equipment Qualification and Process Qualification. All three combine to provide a validated process. While the primary focus of this paper is on Product Qualification, Process Qualification will also be discussed.

1

Guidance for Industry1 Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
I. INTRODUCTION (1) A. Objective (1.1) This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess. In this guidance, the term manufacturing is defined to include all operations of receipt of materials, production, packaging, repackaging, labeling, relabeling, quality control, release, storage and distribution of APIs and the related controls. In this guidance, the term should identifies recommendations that, when followed, will ensure compliance with CGMPs. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes. For the purposes of this guidance, the terms current good manufacturing practices and good manufacturing practices are equivalent.
This guidance was developed within the Expert Working Group (Q7A) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2000. At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States. Arabic numbers in subheadings reflect the organizational breakdown in the document endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2000.
1

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.

1

Guidance for Industry1 Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
I. INTRODUCTION (1)

A. Objective (1.1) This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess. In this guidance, the term manufacturing is defined to include all operations of receipt of materials, production, packaging, repackaging, labeling, relabeling, quality control, release, storage and distribution of APIs and the related controls. In this guidance, the term should identifies recommendations that, when followed, will ensure compliance with CGMPs. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes. For the purposes of this guidance, the terms current good manufacturing practices and good manufacturing practices are equivalent.
This guidance was developed within the Expert Working Group (Q7A) of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2000. At Step 4 of the process, the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United States. Arabic numbers in subheadings reflect the organizational breakdown in the document endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2000.
1

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.

43PRODUCTION

CHAPTER 5 PRODUCTION
Principle
Production operations must follow clearly defined procedures; they must comply with the principles of Good Manufacturing Practice in order to obtain products of the requisite quality and be in accordance with the relevant manufacturing and marketing authorisations.

General
5.1 Production should be performed and supervised by competent people. 5.2 All handling of materials and products, such as receipt and quarantine, sampling, storage, labelling, dispensing, processing, packaging and distribution should be done in accordance

with written procedures or instructions and, where necessary, recorded. 5.3 All incoming materials should be checked to ensure that the consignment corresponds to the order. Containers should be cleaned where necessary and labelled with the prescribed data. 5.4 Damage to containers and any other problem which might adversely affect the quality of a material should be investigated, recorded and reported to the Quality Control Department. 5.5 Incoming materials and finished products should be physically or administratively quarantined immediately after receipt or processing, until they have been released for use or distribution. 5.6 Intermediate and bulk products purchased as such should be handled on receipt as though they were starting materials. 5.7 All materials and products should be stored under the appropriate conditions established by the manufacturer and in an orderly fashion to permit batch segregation and stock rotation. 5.8 Checks on yields, and reconciliation of quantities, should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits. 5.9 Operations on different products should not be carried out simultaneously or consecutively in the same room unless there is no risk of mix-up or cross-contamination. 5.10 At every stage of processing, products and materials should be protected from microbial and other contamination. 5.11 When working with dry materials and products, special precautions should be taken to prevent the generation and dissemination of dust. This applies particularly to the handling of highly active or sensitising materials. 5.12 At all times during processing, all materials, bulk containers, major items of equipment and where appropriate rooms used should be labelled or otherwise identified with an indication of the product or material being processed, its strength (where applicable) and

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5.13 Labels applied to containers, equipment or premises should be clear, unambiguous and in the company’s agreed format. It is often helpful in addition to the wording on the labels to use colours to indicate status (for example, quarantined, accepted, rejected, clean, ...). 5.14 Checks should be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another are connected in a correct manner. 5.15 Any deviation from instructions or procedures should be avoided as far as possible. If a deviation occurs, it should be approved in writing by a competent person, with the involvement of the Quality Control Department when appropriate. 5.16 Access to production premises should be restricted to authorised personnel. 5.17 Normally, the production of non-medicinal products should be avoided in areas and with the equipment destined for the production of medicinal products.

Prevention of cross-contamination in production
5.18 Contamination of a starting material or of a product by another material or product must be avoided. This risk of accidental cross-contamination arises from the uncontrolled release of dust, gases, vapours, sprays or organisms from materials and products in process, from residues on equipment, and from operators’ clothing. The significance of this risk varies with the type of contaminant and of product being contaminated. Amongst the most hazardous contaminants are highly sensitising materials, biological preparations containing living organisms, certain hormones, cytotoxics, and other highly active materials. Products in which contamination is likely to be most significant are those administered by injection, those given in large doses and/or over a long time. 5.19 Cross-contamination should be avoided by appropriate technical or organisational measures, for example: a) production in segregated areas (required for products such as penicillins, live vaccines, live bacterial preparations and some other biologicals), or by campaign (separation in time) followed by appropriate cleaning; b) providing appropriate air-locks and air extraction; c) minimising the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air; d) keeping protective clothing inside areas where products with special risk of crosscontamination are processed; e) using cleaning and decontamination procedures of known effectiveness, as ineffective cleaning of equipment is a common source of cross-contamination;

f) using “closed systems” of production; g) testing for residues and use of cleaning status labels on equipment. 5.20 Measures to prevent cross-contamination and their effectiveness should be checked periodically according to set procedures.

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Validation
5.21 Validation studies should reinforce Good Manufacturing Practice and be conducted in accordance with defined procedures. Results and conclusions should be recorded. 5.22 When any new manufacturing formula or method of preparation is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to yield a product consistently of the required quality. 5.23 Significant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality and/or the reproducibility of the process should be validated. 5.24 Processes and procedures should undergo periodic critical re-validation to ensure that they remain capable of achieving the intended results.

Starting materials
5.25 The purchase of starting materials is an important operation which should involve staff who have a particular and thorough knowledge of the suppliers. 5.26 Starting materials should only be purchased from approved suppliers named in the relevant specification and, where possible, directly from the producer. It is recommended that the specifications established by the manufacturer for the starting materials be discussed with the suppliers. It is of benefit that all aspects of the production and control of the starting material in question, including handling, labelling and packaging requirements, as well as complaints and rejection procedures are discussed with the manufacturer and the supplier. 5.27 For each delivery, the containers should be checked for integrity of package and seal and for correspondence between the delivery note and the supplier’s labels. 5.28 If one material delivery is made up of different batches, each batch must be considered as separate for sampling, testing and release. 5.29 Starting materials in the storage area should be appropriately labelled (see Chapter 5, item 13). Labels should bear at least the following information: — the designated name of the product and the internal code reference where applicable; — a batch number given at receipt; — where appropriate, the status of the contents (e.g. in quarantine, on test, released, rejected); — where appropriate, an expiry date or a date beyond which retesting is necessary. When fully computerised storage systems are used, all the above information need not necessarily be in a legible form on the label. 5.30 There should be appropriate procedures or measures to assure the identity of the contents of each container of starting material. Bulk containers from which samples have been drawn should be identified (see Chapter 6, item 13).

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5.31 Only starting materials which have been released by the Quality Control Department and which are within their shelf life should be used. 5.32 Starting materials should only be dispensed by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labelled containers. 5.33 Each dispensed material and its weight or volume should be independently checked and the check recorded. 5.34 Materials dispensed for each batch should be kept together and conspicuously labelled as such.

Processing operations: intermediate and bulk products
5.35 Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues or documents not required for the current operation. 5.36 Intermediate and bulk products should be kept under appropriate conditions. 5.37 Critical processes should be validated (see "VALIDATION" in this Chapter).

5.38 Any necessary in-process controls and environmental controls should be carried out and recorded. 5.39 Any significant deviation from the expected yield should be recorded and investigated.

Packaging materials
5.40 The purchase, handling and control of primary and printed packaging materials shall be accorded attention similar to that given to starting materials. 5.41 Particular attention should be paid to printed materials. They should be stored in adequately secure conditions such as to exclude unauthorised access. Cut labels and other loose printed materials should be stored and transported in separate closed containers so as to avoid mix-ups. Packaging materials should be issued for use only by authorised personnel following an approved and documented procedure. 5.42 Each delivery or batch of printed or primary packaging material should be given a specific reference number or identification mark. 5.43 Outdated or obsolete primary packaging material or printed packaging material should be destroyed and this disposal recorded.

Packaging operations
5.44 When setting up a programme for the packaging operations, particular attention should be given to minimising the risk of cross-contamination, mix-ups or substitutions. Different products should not be packaged in close proximity unless there is physical segregation.

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5.45 Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines, printing machines and other equipment are clean and free from any products, materials or documents previously used, if these are not required for the current operation. The line-clearance should be performed according to an appropriate check-list. 5.46 The name and batch number of the product being handled should be displayed at each packaging station or line. 5.47 All products and packaging materials to be used should be checked on delivery to the packaging department for quantity, identity and conformity with the Packaging Instructions. 5.48 Containers for filling should be clean before filling. Attention should be given to avoiding and removing any contaminants such as glass fragments and metal particles. 5.49 Normally, filling and sealing should be followed as quickly as possible by labelling. If it is not the case, appropriate procedures should be applied to ensure that no mix-ups or mislabelling can occur. 5.50 The correct performance of any printing operation (for example code numbers, expiry dates) to be done separately or in the course of the packaging should be checked and recorded. Attention should be paid to printing by hand which should be re-checked at regular intervals. 5.51 Special care should be taken when using cut-labels and when over-printing is carried out off-line. Roll-feed labels are normally preferable to cut-labels, in helping to avoid mix-ups. 5.52 Checks should be made to ensure that any electronic code readers, label counters or similar devices are operating correctly. 5.53 Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing. 5.54 On-line control of the product during packaging should include at least checking the following: a) general appearance of the packages; b) whether the packages are complete; c) whether the correct products and packaging materials are used; d) whether any over-printing is correct; e) correct functioning of line monitors. Samples taken away from the packaging line should not be returned. 5.55 Products which have been involved in an unusual event should only be reintroduced into the process after special inspection, investigation and approval by authorised personnel. Detailed record should be kept of this operation. 5.56 Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units produced should be investigated and satisfactorily accounted for before release. 5.57 Upon completion of a packaging operation, any unused batch-coded packaging materials should be destroyed and the destruction recorded. A documented procedure should be followed if uncoded printed materials are returned to stock.

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Finished products
5.58 Finished products should be held in quarantine until their final release under conditions established by the manufacturer. 5.59 The evaluation of finished products and documentation which is necessary before release of product for sale are described in Chapter 6 (Quality Control). 5.60 After release, finished products should be stored as usable stock under conditions established by the manufacturer.

Rejected, recovered and returned materials
5.61 Rejected materials and products should be clearly marked as such and stored separately in restricted areas. They should either be returned to the suppliers or, where appropriate, reprocessed or destroyed. Whatever action is taken should be approved and recorded by authorised personnel. 5.62 The reprocessing of rejected products should be exceptional. It is only permitted if the quality of the final product is not affected, if the specifications are met and if it is done in accordance with a defined and authorised procedure after evaluation of the risks involved. Record should be kept of the reprocessing. 5.63 The recovery of all or part of earlier batches which conform to the required quality by incorporation into a batch of the same product at a defined stage of manufacture should be authorised beforehand. This recovery should be carried out in accordance with a defined procedure after evaluation of the risks involved, including any possible effect on shelf life. The recovery should be recorded. 5.64 The need for additional testing of any finished product which has been reprocessed, or into which a recovered product has been incorporated, should be considered by the Quality Control Department. 5.65 Products returned from the market and which have left the control of the manufacturer should be destroyed unless without doubt their quality is satisfactory; they may be considered for re-sale, re-labelling or recovery in a subsequent batch only after they have been critically assessed by the Quality Control Department in accordance with a written procedure. The nature of the product, any special storage conditions it requires, its condition and history, and the time elapsed since it was issued should all be taken into account in this assessment. Where any doubt arises over the quality of the product, it should not be considered suitable for re-issue or re-use, although basic chemical reprocessing to recover active ingredient may be possible. Any action taken should be appropriately recorded.

CHAPTER 4 DOCUMENTATION
Principle DACCMENTATION
Good documentation constitutes an essential part of the quality assurance system. Clearly written documentation prevents errors from spoken communication and permits tracing of batch history. Specifications, Manufacturing Formulae and instructions, procedures, and records must be free from errors and available in writing. The legibility of documents is of paramount importance.

General

4.1 Specifications describe in detail the requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation. Manufacturing Formulae, Processing and Packaging Instructions state all the starting materials used and lay down all processing and packaging operations. Procedures give directions for performing certain operations e.g. cleaning, clothing, environmental control, sampling, testing, equipment operation. Records provide a history of each batch of product, including its distribution, and also of all other relevant circumstances pertinent to the quality of the final product. 4.2 Documents should be designed, prepared, reviewed and distributed with care. They should comply with the relevant parts of the manufacturing and marketing authorisation dossiers. 4.3 Documents should be approved, signed and dated by appropriate and authorised persons. 4.4 Documents should have unambiguous contents; title, nature and purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check. Reproduced documents should be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process. 4.5 Documents should be regularly reviewed and kept up-to-date. When a document has been

revised, systems should be operated to prevent inadvertent use of superseded documents. 4.6 Documents should not be handwritten; although, where documents require the entry of data, these entries may be made in clear, legible, indelible handwriting. Sufficient space should be provided for such entries. 4.7 Any alteration made to the entry on a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded. 4.8 The records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of medicinal products are traceable. They should be retained for at least one year after the expiry date of the finished product. 4.9 Data may be recorded by electronic data processing systems, photographic or other reliable means, but detailed procedures relating to the system in use should be available and the accuracy of the records should be checked. If documentation is handled by electronic data processing methods, only authorised persons should be able to enter or modify data in the computer and there should be a record of changes and deletions; access should be restricted by passwords or other means and the result of entry of critical data should be independently checked. Batch records electronically stored should be protected by back-up transfer on magnetic tape, microfilm, paper or other means. It is particularly important that the data are readily available throughout the period of retention.

Documents required
Specifications
4.10 There should be appropriately authorised and dated specifications for starting and packaging materials, and finished products; where appropriate, they should be also available for intermediate or bulk products. Specifications for starting and packaging materials 4.11 Specifications for starting and primary or printed packaging materials should include, if applicable: a) a description of the materials, including: — the designated name and the internal code reference; — the reference, if any, to a pharmacopoeial monograph; — the approved suppliers and, if possible, the original producer of the products; — a specimen of printed materials; b) directions for sampling and testing or reference to procedures; c) qualitative and quantitative requirements with acceptance limits; d) storage conditions and precautions; e) the maximum period of storage before re-examination. Specifications for intermediate and bulk products 4.12 Specifications for intermediate and bulk products should be available if these are purchased or dispatched, or if data obtained from intermediate products are used for the evaluation of the finished product. The specifications should be similar to specifications for starting materials or for finished products, as appropriate. Specifications for finished products 4.13 Specifications for finished products should include: a) the designated name of the product and the code reference where applicable; b) the formula or a reference to; c) a description of the pharmaceutical form and package details; d) directions for sampling and testing or a reference to procedures; e) the qualitative and quantitative requirements, with the acceptance limits; f) the storage conditions and any special handling precautions, where applicable; g) the shelf-life.

Manufacturing Formula and Processing Instructions

Formally authorised Manufacturing Formula and Processing Instructions should exist for each product and batch size to be manufactured. They are often combined in one document. 4.14 The Manufacturing Formula should include: a) the name of the product, with a product reference code relating to its specification; b) a description of the pharmaceutical form, strength of the product and batch size; c) a list of all starting materials to be used, with the amount of each, described using the designated name and a reference which is unique to that material; mention should be made of any substance that may disappear in the course of processing; d) a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable. 4.15 The Processing Instructions should include:

a) a statement of the processing location and the principal equipment to be used; b) the methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilising); c) detailed stepwise processing instructions (e.g. checks on materials, pre-treatments, sequence for adding materials, mixing times, temperatures); d) the instructions for any in-process controls with their limits; e) where necessary, the requirements for bulk storage of the products; including the container, labelling and special storage conditions where applicable; f) any special precautions to be observed.

Packaging Instructions

4.16 There should be formally authorised Packaging Instructions for each product, pack size and type. These should normally include, or have a reference to, the following: a) name of the product; b) description of its pharmaceutical form, and strength where applicable; c) the pack size expressed in terms of the number, weight or volume of the product in the final container; d) a complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types, with the code or reference number relating to the specifications of each packaging material; e) where appropriate, an example or reproduction of the relevant printed packaging materials, and specimens indicating where to apply batch number references, and shelf life of the product; f) special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before operations begin; g) a description of the packaging operation, including any significant subsidiary operations, and equipment to be used; h) details of in-process controls with instructions for sampling and acceptance limits.

Batch Processing Records

4.17 A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved Manufacturing Formula and Processing Instructions. The method of preparation of such records should be designed to avoid transcription errors. The record should carry the number of the batch being manufactured. Before any processing begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned process, and that equipment is clean and suitable for use. During processing, the following information should be recorded at the time each action is taken and, after completion, the record should be dated and signed in agreement by the person responsible for the processing operations: a) the name of the product; b) dates and times of commencement, of significant intermediate stages and of completion of production; c) name of the person responsible for each stage of production; d) initials of the operator of different significant steps of production and, where appropriate, of the person who checked each of these operations (e.g. weighing); e) the batch number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added); f) any relevant processing operation or event and major equipment used; g) a record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained; h) the product yield obtained at different and pertinent stages of manufacture; i) notes on special problems including details, with signed authorisation for any deviation from the Manufacturing Formula and Processing Instructions.

Batch Packaging Records

4.18 A Batch Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the Packaging Instructions and the method of preparation of such records should be designed to avoid transcription errors. The record should carry the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained. Before any packaging operation begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the

planned packaging operations, and that equipment is clean and suitable for use. The following information should be entered at the time each action is taken and, after completion, the record should be dated and signed in agreement by the person(s) responsible for the packaging operations: a) the name of the product; b) the date(s) and times of the packaging operations; c) the name of the responsible person carrying out the packaging operation; d) the initials of the operators of the different significant steps; e) records of checks for identity and conformity with the packaging instructions including the results of in-process controls; f) details of the packaging operations carried out, including references to equipment and the packaging lines used; g) whenever possible, samples of printed packaging materials used, including specimens of the batch coding, expiry dating and any additional overprinting; h) notes on any special problems or unusual events including details, with signed authorisation for any deviation from the Manufacturing Formula and Processing Instructions; i) the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of obtained product, in order to provide for an adequate reconciliation.

Procedures and records
Receipt
4.19 There should be written procedures and records for the receipt of each delivery of each starting and primary and printed packaging material. 4.20 The records of the receipts should include: a) the name of the material on the delivery note and the containers; b) the "in-house" name and/or code of material (if different from a); c) date of receipt; d) supplier’s name and, if possible, manufacturer’s name; e) manufacturer’s batch or reference number; f) total quantity, and number of containers received; g) the batch number assigned after receipt; h) any relevant comment (e.g. state of the containers). 4.21 There should be written procedures for the internal labelling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate.

Sampling

4.22 There should be written procedures for sampling, which include the person(s) authorised to take samples, the methods and equipment to be used, the amounts to be taken and any precautions to be observed to avoid contamination of the material or any deterioration in its quality (see Chapter 6, item 13).

Testing

4.23 There should be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed should be recorded (see Chapter 6, item 17).

Other
4.24 Written release and rejection procedures should be available for materials and products, and in particular for the release for sale of the finished product by the Qualified Person(s) in accordance with the requirements of Article 51 of Directive 2001/83/EC1. 4.25 Records should be maintained of the distribution of each batch of a product in order to facilitate the recall of the batch if necessary (see Chapter 8). 1 Article 55 of Directive 2001/82/EC 4.26 There should be written procedures and the associated records of actions taken or conclusions reached, where appropriate, for: — validation; — equipment assembly and calibration; — maintenance, cleaning and sanitation; — personnel matters including training, clothing, hygiene; — environmental monitoring; — pest control; — complaints; — recalls; — returns.

4.27 Clear operating procedures should be available for major items of manufacturing and test equipment. 4.28 Log books should be kept for major or critical equipment recording, as appropriate, any validations, calibrations, maintenance, cleaning or repair operations, including the dates and identity of people who carried these operations out. 4.29 Log books should also record in chronological order the use of major or critical equipment and the areas where the products have been processed.