 Help required for dedicated site

I have been given responsibility for developing a cleaning validation strategy for a dedicated[/u] facility producing a single ocular implant[/u][/b] and I need some advice as I am new to the field of cleaning validation.
The product we make is an ocular implant consisting of a 2.5mg tablet containing 0.59mg of steroid in a PVA based delivery module. Total implant weight is 9.5mg. The implant releases the steroid over a 36 month period with the target dose of 0.3ug/day.
In the assembly stage the implant is constructed using 120 assembly plates, each plate has a surface area = 8.8cm2, each of which hold 12 implants.
Total number of implants made = 120*12 = 1440
The plates are then washed using a detergent.
I need to determine the maximum allowable detergent residue on the plates & this is where I run into difficulties.

Detergent LD50 (Oral,Rat)= 2000mg/kg
Total surface area of plates, 120 x 8.8 = 1056cm2
NOEL=20000.0005 = 1.0mg/kg
Acceptable Daily Intake (ADI) = 1.0mg/kg
70kg*(1/10,000) = 0.007mg

For the Maximum Allowable Carryover MAC = (ADIB)/R
where B smallest batch size & R denotes largest daily dose made in the equipment.
In my case, do I use B as equal to the total number of implants made multiplied by the weight of the active tablet, ie 1440
2.5mg = 3600mg
and can I put R as being equal to the target dose of 0.3ug/day (CASE 1) or would it be a case where it can be assumed that all the steroid is released in a single dose, ie 0.59mg (CASE 2)
CASE 1 result MAC = [(0.007mg3600mg)]/0.0003mg = 84,000mg
CASE 2 result MAC = [(0.007mg
3600mg)]/0.59mg = 42.7mg
Or can I put B (smallest batch size) as being a single assembly plate producing 12 implants, 122.5mg = 30mg
giving: CASE 3 MAC = [(0.007mg
30mg)/0.0003mg] = 700mg
or CASE 4 MAC = [(0.007mg*30mg)/0.59mg] = 0.36mg

The intended swab area is 25cm2, and the absorbing solution volume is 45cm3.
Thus giving an analytical surface limit (ASL)
[(MAC/total area)swabbing area]/Volume of desorption solvent
for the 4 cases of:
CASE 1 MAC = 84,000mg, total surface area of 120
8.8cm2 = 1056cm2
ASL = (84,000mg/1056cm2)*25cm2 = 1989mg = 1989000ug/45cm3 =
44200ppm

CASE 2 MAC = 42.7mg, total surface area of 120*8.8cm2 = 1056cm2
ASL = (42.7mg/1056cm2)*25cm2 = 1.0mg = 1000ug/45cm3 = 22ppm

CASE 3 MAC = 700mg, total surface area of 8.8cm2 (single assembly plate)
ASL = (700mg/8.8cm2)*25cm2 = 1989mg = 1989000ug/45cm3 = 42000ppm

CASE 4 MAC = 0.36mg, total surface area = 8.8cm2
ASL = (0.36mg/8.8cm2)*25cm2 = 1.0mg = 1000ug/45cm3 = 22ppm

I apologise for the length of this post but this is really causing me sleepless nights. Any help would be gratefully received.

Dear Cleanerguy,

Please don’t stress yourself with unnecessary worries, we are here for you .

To start with, for the determination of Maximum Allowable Carry-Over (MACO) for detergent/cleaning agent residues two methods could be used (a) Method based on Toxicity of the contaminant (the one which you have been trying to solve) and (b) 10 ppm method. Calculation for both the methods is simple doesn’t require working around with so many cases.

MACO for detergent can be determined by using following formulae:

b Toxicity method[/b]

mg of detergent residue permitted per 25 sq cm of swab area = (NOEL x SF x K x U)/(J x L)

Where,
NOEL = No observed Effect Level [NOEL = LD50 X (W/E)]
LD50 = Lethal Dose 50 in mg/kg animal for detergent (you need to provide justification for using oral LD50 for ocular implants. I would suggest you to use ocular LD50 value, if available).
E = Empirical Constant = 2000
W = Average human body weight (kg)
SF = Safety Factor = 0.0001 (for Ocular preparations)
J = Maximum number of dosage units of Product B (i.e. ocular implant) applied per day (worst case = 2 assuming that the ocular implants are used in both the eyes).
K = Number of dosage units per batch of final mixture of Product B (i.e. total implants made = 1440).
L = Equipment surface area in common between Product A (i.e. detergent) & Product B expressed as cm² (= 1056cm2)
U = Swab area (= 25 cm²/swab)

Using above formula limit (for detergent) based on toxicity criterion would be:

NOEL = 2000mg/kg x (70 kg/2000) = 70 mg

mg of detergent residue permitted per 25 sq cm = (70 x 0.0001 x 1440 x 25)/(2 x 1056) = 0.119 mg/cm2.

b 10 ppm method[/b]

mg of detergent residue permitted per 25 sq cm of swab area = R x (N/L) x U

Where
R = 10 mg of detergent/kg Product B
N = Number of kgs per batch of final mixture of Product B (=1440 x 9.5 mg = 13680 mg = 0.01368 kg)
L = Equipment surface area in common between Product A (i.e. detergent) & Product B expressed as cm² (= 1056cm2)
U = Swab area (= 25 cm²/swab)

mg of detergent residue permitted per 25 sq cm = 0.003238636 mg/cm2

Hence, based on above calculations MACO for detergent residue would be = 0.003238636 mg/cm2 (lowest of the two values).

For calculating analytical limit (AL) you have to use this: AL = (MACO x R)/V

Where, R = recovery factor and V = Extraction solvent volume/absorbing solution volume (in your case this = 45 ml).

Hope I was able to put the solution across, if not sure please ask.

Hi Ovais