basic concepts of cleaning validation

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CLEANING VALIDATION

BY

ABHISHEK MORRIS

CLEANING VALIDATION Background

Through its regulatory activities, FDA became aware in the early 1960's of the potential health hazards of product residues

FDA inspections revealed manufacturing practices leading to contamination of certain drug preparations with penicillin

Amendments to drug regulations for current good manufacturing practices (GMPs) were published January 29, 1965 for the control of cross contamination by penicillin.

In October 1965 the Division of Antibiotics and Insulin Certification, now the National Center for Antibiotics Analysis (NCAA), published methods for penicillin analysis, titled “Procedures for Detecting and Measuring Penicillin Contaminants in Drugs”.

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CLEANING VALIDATION Background

In 1963 The FDA published a Guide to Inspections ”Validation of Cleaning Processes”, intended to cover equipment cleaning for chemical residues only. In this document FDA outlines what is expected:

a) Expects firms to have written procedures (SOPs) detailing the cleaning processes.

b) Expects firms to have written general procedures on how cleaning processes will be validated.

c) Expects firms to conduct the validation studies in accordance with the protocols and to document the results of studies.

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CLEANING VALIDATION Definition

EU and Australian Code of GMP

“Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products”.

21 CFR 211.176, Penicillin contamination, states:“If a reasonable possibility exists that a non-penicillin drug product has been exposed to cross-contamination with penicillin, the non-penicillin drug product shall be tested for the presence of penicillin. Such drug product shall not be marketed if detectable levels are found when tested according to procedures specified in ‘Procedures for Detecting and Measuring Penicillin Contamination in Drugs”.

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CLEANING VALIDATION Examples of cGMP requirements

21 CFR 211.67 (a)

“Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements”.

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CLEANING VALIDATION Examples of cGMP requirements

EU and Australian CMP, 5.18

“Contamination of a starting material or of a product by another material or product mustbe avoided….... The significance of this risk varies with the type of contaminant and of product being contaminated. Amongst the most hazardous contaminants are highly sensitizing materials, biological preparations containing living organisms, certain hormones, cytotoxics, and other highly active materials”.

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CLEANING VALIDATIONExamples of cGMP requirements

WHO, Annex 4, 4.11

“It is of critical importance that particular attention is paid to the validation of analytical test methods, automated systems and cleaning procedures”.

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CLEANING VALIDATION Principle

Pharmaceutical products and active pharmaceutical ingredients (APIs) can be contaminated by other pharmaceutical products or APIs, by cleaning agents, by micro-organisms or by other material (e.g. air-borne particles, dust, lubricants, raw materials, intermediates).

In many cases, the same equipment may be used for processing different products. To avoid contamination of the following pharmaceutical product, adequate cleaning procedures are essential.

Cleaning procedures must strictly follow carefully established and validated methods of execution. This applies equally to the manufacture of pharmaceutical products and active pharmaceutical ingredients (APIs).

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CLEANING VALIDATION General requirements

Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to noncontact parts into which product may migrate. For example, seals, flanges, mixing shaft, fans of ovens, heating elements etc.

Cleaning procedures for product changeover in the case of marketed products should be fully validated.

Cleaning procedures for products and processes which are very similar, do not need to be individually validated.”.

Generally in case of batch-to-batch production it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined.

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It is considered acceptable to select a representative range of similar products and processes concerned and to justify a validation program which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the “worst case” can then be carried out which takes account of the relevant criteria. This practice is termed "Bracketing” or “grouping

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At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.

Raw materials sourced from different suppliers may have different physical properties and impurity profiles. Such differences should be considered when designing cleaning procedures, as the materials may behave differently.

It is usually not considered acceptable to "test until clean". This concept involves cleaning, sampling and testing, with repetition of this sequence until an acceptable residue limit is attained. For the system or equipment with a validated cleaning process, this practice of "test until clean" should not be required. The practice of "test until clean" is not considered to replace the need to validate cleaning procedures.

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Products which simulate the physicochemical properties of the substance to be removed may be used instead of the substances themselves, where such substances are either toxic or hazardous.

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CLEANING VALIDATION Some general questions

Several questions should be addressed when evaluating the cleaning process. For example:

a) At what point does a piece of equipment or system become clean?

b) What does visually clean mean?

c) Does the equipment need to be scrubbed by hand?

d) What is accomplished by hand scrubbing rather than just a solvent wash?

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CLEANING VALIDATION Some general questions

e) How variable are manual cleaning processes from batch to

batch and product to product?

f) What is the most appropriate solvent or detergent?

g) Are different cleaning processes required for different

products in contact with a piece of equipment?

h) How many times need a cleaning process be applied to

ensure adequate cleaning of each piece of equipment?

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CLEANING VALIDATIONEquipment cleaning strategies

Dedicated

Campaign

Common

Cleaning of processing areas also requires validation. The general principles outlined in this presentation are applicable. Sampling methods and limits should be appropriate to the material be processed.

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CLEANING VALIDATIONSome points to consider

Required written procedures that are standardized

Required written protocols

Justification for limits set

Equipment and product mix for common and dedicated equipment

Use of manual verses automatic cleaning procedures, such as CIP

Ongoing program of monitoring effectiveness

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CLEANING VALIDATIONSome equipment & product considerations

Use of “worst case” (e.g. smallest batch size, smallest number of maximum daily doses, hardest to clean) product as a marker for easier other products

Grouping of products

For example grouping based on; those products capable of causing the largest possible problems if contaminated, or if they contaminate other products; drug solubility and; equipment.

Identification of items of equipment that contribute most to cross contamination of the next product

Identification of “worst case” locations in equipment , i.e. the design of the equipment should be carefully examined.

Critical areas (those hardest to clean) should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place (CIP) systems.

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CLEANING VALIDATIONSome equipment & product considerations

Dedicated equipment should be used for products which are difficult to remove (e.g. tarry or gummy residues in the bulk manufacturing), for equipment which is difficult to clean (e.g. bags for fluid bed dryers), or for products with a high safety risk (e.g. biologicals or products of high potency which may be difficult to detect below an acceptable limit).

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CLEANING VALIDATIONResidue detection

Visual checking

- Suitable for dedicated equipment

- Include in all protocols and routine monitoring

Chemical tests

- Specific methods such as; high performance liquid chromatography (HPLC), ion selective electrodes, flame photometry, derivative UV spectroscopy, enzymatic detection and titration

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Methods validation and recovery studies

Involves the use of the sampling and detection method on known spiked surfaces at representative levels, typically spiked at 50%, 100% and 150% of the acceptable limit and at lower expected actual levels to show linearity with documented % recovery as analyzed and to determine the limit of detection and limit of quantitation. Ideally the expected

values and limits should be multiples of the limits of

quantization.

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Chemical tests

a) Non-specific methods that detect the presence of a blend of ingredients such as: total organic carbon, pH, and conductivity.

b) Specific methods. The FDA prefers specific methods, but will accept non-specific methods with adequate rationales for their use.

c) Chemical limits can be expressed as a maximum concentration in the next product (ug/ml), amount per surface area (ug/cm2), amount in a swab sample (ug or ug/ml), maximum carryover in a train (mg or g), or concentration in rinse water (ug/ml). There can be a calculated safety based acceptance limit, a lower internal action level, and a lower process control level based on actual manufacturing and measuring experience.

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c) Chemical limits can be expressed as a maximum concentration in the next product (ug/ml), amount per surface area (ug/cm2), amount in a swab sample (ug or ug/ml), maximum carryover in a train (mg or g), or concentration in rinse water (ug/ml). There can be a calculated safety based acceptance limit, a lower internal action level, and a lower process control level based on actual manufacturing and

measuring experience.

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CLEANING VALIDATIONMicrobial considerations

a) Endotoxins

b) TAMC

c) The existence of conditions favourable to reproduction of microorganisms (e.g. moisture, temperature, crevices and rough surfaces) and

the time of storage should be considered. The aim should be to prevent excessive microbial contamination.

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CLEANING VALIDATIONMicrobial considerations

d) The period and when appropriate, conditions of storage of equipment before cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation.

e) In general, equipment should be stored dry, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.

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CLEANING VALIDATIONDetergent considerations

The efficiency of cleaning procedures for the removal of detergent residues should be evaluated. Acceptable limits should be defined for levels of detergent after cleaning. Ideally, there should be no residues detected. The possibility of detergent breakdown should be considered when validating

cleaning procedures.

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CLEANING VALIDATIONDetergent considerations

The composition of detergents should be known.

If such information is not available, alternative detergents should be selected whose composition can be defined. As a guide, food regulations may be consulted. The manufacturer should ensure that he is notified by the detergent supplier of any critical changes in the formulation of the

detergent.

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CLEANING VALIDATIONSampling methods principle

There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling.

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CLEANING VALIDATIONSampling methods principle

Direct Surface Sampling (swabbing)The suitability of the material to be used for sampling and of the sampling medium should be determined. The ability to recover samples accurately may be affected by the choice of sampling material. It is important to ensure that the sampling medium and solvent are satisfactory and can be readily used.

Rinse SamplesRinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant.

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CLEANING VALIDATIONSampling methods considerations

Swab samplesa) Reliable determination of residueb) Locations must be carefully defined (use difficult to clean locations). c) Extrapolate sample area to whole aread) Method recovery must be validated (e.g. spiking studies, recovery target, LOD and LOQ, precision, linearity and selectivity)

Rinse samplesa) May be helpful where sites are inaccessible to swabsb) Useful for cleaning agent residuesc) Must define volumes of rinse agent usedd) Method recovery must be validated

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CLEANING VALIDATIONSampling method considerations

e) The choice of containers used in the analysis of samples is very important. It has been shown that, in very dilute solutions, surfactants can adsorb onto the surfaces of sample vials. This will produce artificially low results in the analysis. Appropriate spiking studies should be performed to ensure that this phenomenon is not occurring and will not interfere with the

analytical method.

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CLEANING VALIDATIONSelection of limits - principle

Establishment of Limits

a) The pharmaceutical company's rationale for selecting limits for product residues should be logically based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable.

b) The approach for setting limits can be:i) Product specific Cleaning Validation for all products, orii) Grouping into product families and choosing a "worst case" productiii) Grouping into groups of risk (e.g. very soluble products, similar potency, highly toxic products, difficult to detect etc.).

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Carry-over of product residues should meet defined criteria, for example the most stringent of the following three criteria:

(a) No more than 0.001 (0.01%)of the normal therapeutic dose of any product (or minimum dose if there are number formulations with different strengths) will appear in the maximum daily dose of the following product

(b) No more than 10 ppm of any product will appear in another product,

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(c) No quantity of residue should be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible

(d) For certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products.

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e) It should not be assumed that the contaminant will be uniformly distributed throughout a system. The assumption that a residual contaminant would be worn off the equipment surface uniformly, or that the contamination might only occur at the beginning of the

batch, should not be made.

f) In establishing residual limits, it may not be adequate to focus only on the principal reactant since chemical variations (active decomposition materials) may be more difficult to remove.

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CLEANING VALIDATIONSelection of limits

Some points to consider:Generala) Regulatory agencies do not set limits

b) Use of dedicated equipment wherever possible, e.g. scoops, FBP, blenders, compression machines etc.

c) Total surface areas of all common equipment used

d) Validation data should support a conclusion that residues have been reduced to an acceptable level

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Some points to consider:.Visually cleana) Accepted by FDA for cleaning between batches of the same product or different lots of the same intermediate in a bulk process

b) Useful for both equipment and walls, floors etc. of processing areas

c) Note that for many residues the visual detection limit is in the order of 1-4 ug/cm2. It is possible that the visually clean criteria will be the most stringent criteria.

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Some points to consider:.

Medical dosage level is probably the most common basis for limits calculations in the pharmaceutical industry. It is based on allowing a certain fraction of a daily dose to carry over to a daily dose of a following product. The fraction that reduces the dosage is referred to as a safety factor or a risk assessment factor and takes the form of a fraction such as 1/100th, 1/1000th, or 10,000th of the original daily dose.

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A commonly used limit is no more than one thousandth (0.001) of the minimum daily dose of a current product will appear in the maximum daily dose of a subsequent

Product

Where a there is a large product range, to reduce swabbing work load, one approach is to identify which product is a worst case (e.g. based on the smallest number of maximum

daily doses, i.e. batch size divided by maximum daily dose).

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a) No more than 10ppm of any product will appear in another product

i) This has its origins in the regulations that apply to food products in

the US.

ii) Also used in the USP for hazardous substances, such as heavy

metals and impurities.

iii) Assumes that residue is as harmful as a hazardous substance

iv) Useful for materials for which no toxicological data is available,

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b) In the case of small final filling equipment such as filling needles for vials or tablet punches and dies, it may be necessary to do separate residue studies on the filling needles or punches and dies to be sure that there was not enough residue just on that equipment to contaminate the first few bottles or tablets of the next batch with the maximum allowable carryover limit (MACO) of the previous

product.

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CLEANING VALIDATION Protocol

The Cleaning Validation Protocol should include, for example, the following:

a) The objective of the validation process.

b) Responsibilities for performing and approving the validation study

c) Description of the equipment to be used.

d) The interval between the end of production and the beginning of the cleaning procedures.

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CLEANING VALIDATION Protocol

e) Cleaning procedures to be used for each product, each manufacturing system or each piece of equipment.

f) The number of cleaning cycles to be performed consecutively.

g) Any routine monitoring requirement.

h) Sampling procedures, including the rationale for why a certain sampling method is used.

i) Clearly defined sampling locations.

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CLEANING VALIDATIONProtocol

j) Data on recovery studies where appropriate,

k) Analytical methods including the limit of detection and the limit of quantitation of those methods or reference to them

l) Acceptance criteria and limits

m) Details of of product “grouping”

n) When Re-validation will be required.

o) A Final Validation Report. The conclusions of this report should state if the cleaning process has been validated successfully.

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CLEANING VALIDATIONEquipment considerations

In the case of a product changeover, the total surface area of equipment common to each product has to be determined.

Assuming a swab area of 10 cm2 , the total amount of residue present is determined by dividing the equipment surface area (cm2 ) by 10 and multiplying this result by the residue quantity. This is repeated for all common equipment in the “train” and the total residue calculated by

adding all results together.

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We first manufacture product A and then product B, "What is an acceptable level of product A to carry over and be present in product B and yet not cause a medical effect in the patient consuming product B?" The math is.

The maximum allowable carryover, MACO

= (allowable carryover into a single daily dose of next product) x (# of daily doses in complete batch of next product)

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CLEANING VALIDATION Selection of limits

or,

MACO = ( allowable carryover into a single daily dose of next product) x (batch size of next product divided by daily dose of next product)

The allowable carryover of product A into a single dose of product would be:

(Daily dose of A) divided by (Safety Factor)

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Thus, the total maximum allowable carryover depends on four variables:

The daily dose of product AThe safety factor selectedThe batch size of product BThe daily dose of product B

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Example 1

Let's suppose, for the present example, that we have two orally administered products (A and B) manufactured using the same equipment. Product A is formulated in two strength, a 500mg dose and a 850mg dose, each dose is given once a day. The maximum daily dose of Product B is 8 tablets and the batch

size is 320,000 tablets.

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Example 1

The minimum daily dose of Product A, which is 500mg, is used in the following calculation.

MACO= (Minimum daily dose of Product A/safety factor of 1000) x (# of daily doses in complete batch of next product)

MACO = 500/1000 x 320,000/8 = 20g

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Example 2

Let's suppose, for the present example, that we have five products (A, B, C, D, and E) in the current product grouping, and they are all products given by the oral route of administration. Let's further assume that the group of five all has different dosages and batch sizes as represented in the next

slide.

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Example 2 PRODUCT MAX BATCH DAILY DOSE mg SIZE KgA 100 50B 150 100C 200 100D 250 10E 300 150

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Example 2 The limits calculated will depend upon the specific sequence of products manufactured, thus there are 20 different combinations and permutations of possible manufacturing sequences for only a five-product group. Even if the initial product is specified, then there could be four other products manufactured subsequently, thus four different limits. For this reason, many companies use an equation which takes into account the "worst case" situations for all products in the same group.

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Example 2 If Product A is selected as the initial product. In order to calculate a limit for carryover of product A into any other product, we could use the following equation:MACO= (DTDA) x (WC#D)/SFMACO = Maximum allowable carryoverDTDA = Daily therapeutic dose of product AWC#D = Worst case # dosesSF = Safety factor (usually 1,000)

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Example 2 The worst case number of doses in the following product would be determined by a combination of the largest daily dose (active plus excipients) of any of the other product in the group and the smallest batch size of any other product in the group by the relationship:

Worst case = Smallest batch size* Largest daily dose** of any other product in group

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Example 2

The data show in Slide 60 for the current group of five products shows that Product E has the largest Daily Dose Weight (300 mg) and Product D has the Smallest Batch Size (10 Kg) of the product group. Thus the Worst Case Number of

Doses would be:

Worst case # doses = 10,000,000 mg = 33,333 doses

300 mg/dose

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Example 2 The 10 Kg was converted to mg so that the units would agree. This value would now be substituted back into the MACO calculation with the following results:

MACO = DTDA x WC#D in following product SFMACO = 10 mg x 33,333 = 333 mg 1000We can now perform a 'worst case' calculation for each of the five products in the group and this would reduce the number of calculations from twenty down to five. The resulting calculations for the group of five products are shown in the next slide.

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Example 2 PRODUCT MACO for all products in group mgA 333B 990C 3330D 6660E 16650

The MACO for Product A, shown in slide 55, is the maximum residue that can be present on the surfaces of all common equipment in the train. This is regardless of which product is being produced and which product is produced next.

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Example 3

The limit of Product A (which contains the most potent active) in Product B (which contains the least number of maximum daily doses per batch)

MACO = D x E mg

where:

D = The minimum daily dose of the smallest strength of Product A

E = The maximum number of daily doses per batch of Product B

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Example 3

In a tablet product grouping product A is the most potent. One thousandth of the minimum daily dose is 0.0006 mg.

Product D has the least number of maximum daily doses per batch, 50,000.

The MACO limit is 0.0006 x 50,000 = 30mg

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Example 3From swabbing, the total residue found on all common

equipment is 0.600 mg.

Based on the data, the cleaning procedure is acceptable regardless of which product is being produced and which

product is produced next.

ABHISHEK MORRIS

THANKYOU

ABHISHEK MORRIS

basic concepts of cleaning validation

Education

equipment cleaning

cleaning intervals

cleaning agents

adequate cleaning procedures

approved cleaning procedure

validation studies

validation program

penicillin contamination