Campaign production

good morning-
Please,how can i do a campaign production in comun areas with many rooms .Can i do the campaignproduction in one or two rooms,and use the another rooms in other product.??
The rooms concern to the same area, and they share extraction and suplply air system.
Many thanks for your reply.
Regards-Paul

When you have 2 different rooms:

-You can do campaign production
-You need different Air handling units with differential pressures that prevent cross contamination
-You must have different Operating staff & Quality assurance staff.
-You packing area will be common but different packing table for prevention of product mix-up while packing.
-Your primary processing like shifting, Blending, Mixing, Drying, Filtration should always be seperate and should be properly marked to prevent product mix-ups.
-Your primary packing material like Bottles and Ropp caps and Vials , Stoppers & Flipoff seals must enter seperately

When you do not have different rooms and when you perform in Campaign

-All untensils must be cleaned and verified for traces of previous materials
-Dispensing systems must be cleaned
-Areas must be cleaned and proper line clearence procedures must be in place
-The dresses must be cleaned and washed and Dried.
-Seperate set of gloves must be used .
-The primary contact parts like Punches, Dyes, Feeders, Drier plates, Tubes, Filling heads must be dedicated–what ever said and done they cannot be cleaned even by robust cleaning methods.
-All previous packing materials to Stage identification lables must be cleared and a robust line clearence should be inplace.
-All tanks, Kettles, Driers, Mixers, FBD, Blenders, Impellers, Homogenisers, Colloidalmills, Coating equiments, Coating guns etc must be cleaned and until a properly signal is obtained from QA/QC -it should not be used.

Regards

can any one provide me guidelines for cleaning validation in solid dosage form (Tablets/Capsules) facility.

Regards
ANIL SAXENA

Mr.Anil/duke77,
I think the document attached here gives a basic Idea about Tablets,Capsules & Liquid.
This shall be my last post in this site.
I must change my Documentation procedures and the way I present.
I shall come back only after 2 or 3 months after retroinspection.
I apologise to duke77 that I could not help much this time.
Hope some one will share the document you are looking for very soon.
Bye


CVP For tablet (106.5 KB)

Anil,

Cleaning validation is a vast topic but I think you’ll get a fairly good idea from the document Mr. Durga has attached.

Most important step in cleaning validation is to document the cleaning process. The major concern of regulatory agencies has targeted pieces of equipment that will be cleaned manually, and where the primary responsibility for the removal of product residues lies with the cleaning operator. In the case of manual cleaning methods, the effectiveness of cleaning depends upon the design of the procedure and the commitment of the operators to follow that procedure. This requires a well-explained SOP, personnel training, and operator commitment. With all three elements present, reproducibility of the results in terms of removal of product residues from equipment surfaces can be achieved.

One of the critical steps is the swabbing or lift up technique which should be validated i.e. to find out how many swabbing strokes and in which directions (horizontal/vertical?) would be required to collect the sample. Other important factors are the LOD (limit of detection) and LOQ (Limit of Quantitation) in analysis.

If you have many different products, you can use the “Matrix approach” which means that a number of products (produced in the same or some common equipment) will be validated to a level of cleanliness that is acceptable for all products which may follow in the same or some common equipment.

Your cleaning validation (CLV) should be based on worst case scenario i.e. Toxicity and Solubility profile.

In matrix approach, series of equipments involved in manufacturing of the worst case products should be validated and it can be assumed since these difficult to clean products are removed from all the equipments therefore all other products will also be cleaned.
Acceptance criteria for API’s for these products is calculated considering all other product batches to be manufactured using all or common equipments.

Please note that if a new product is introduced in the matrix, a documented evaluation will be done to confirm that the worst case will not be changed, and if the new addition becomes the worst case, validation will be required and if it is not the worst case then a minimum of one cleaning run is required.

Regards,

Thank you Mr.Shoaib Khan and Mr.DURGA PRASAD for your important information.

But i want to GUIDELINES (USFDA, MHRA & other regulatory agency) for cleaning validation of Solid dosage facility (Tablets & Capsules), because

we have cleaning procedure & cleaning validation procedure, we have done cleaning method validation (LOD, LOQ, Swab recovery etc) and we do cleaning validation based on MACO Calculation (As per product matrix & common equipments [we have six Granulation areas so we have six product matrix and four equipments matrix because three granulation areas have same equipments]) so we have six worst case products- one for each Granulation area. we select worst case based on low solubility, high potency, larges daily dose & lowest batch size.

my company is new and we are going for USFDA, MHRA, ANVISA and other audits.

we have reference of PDA Technical Report No. 29.

my questions are

  1. is our policy is correct that we have six worst case product ?
  2. is PDA Technical Report No. 29 reference is acceptable by Regulatory agencies auditors or they want other guidelines that we need to follow ?
    3.We are doing cleaning validation(three batches) for Worst case product and cleaning verification(one batch) for other than worst case product, is it require to verify every product ?
    4.During MACO calculation we add new product in matrix & if worst case is not changed then MACO limit is worst case limit or new calculated limit (this may be lower or higher than worst case limit) ?
    5.we don’t have any commercial production (we manufacture only validation batches), at the time of commercial production our product batch sizes will increase so again require to revalidation of cleaning procedure or not ?

we want guidelines (including PDA Technical Report No. 29 final copy) or web link.

Regards

ANIL SAXENA

Mr.Saxena,
Its very difficult to get a Unauthorized PDA Technical Report 29. And its illegal.
Best thing is that ask your company to become a member in PDA by paying membership fees of 150 to 250$/Year and they can purchase this report or your company can purchase this by paying 150$ directly from PDA Site by downloading that document

I can mention here what FDA & Regulating agencies expect about Cleaning validation:

[b][COLOR=“darkred”]FDA, in its guidelines for cleaning validation, has clearly expressed expectations that
industries have to fulfill. The basic requirements, as per FDA, are as follows:

  1. A written procedure on how cleaning processes will be validated
  2. Clearly outlined responsibility for performing and approving validation study,
    acceptance criteria, and revalidation requirement
  3. Approved written protocols describing the study to be performed, system or piece
    of equipment, sampling procedures, testing methods, and so on
  4. Execution of the protocols in accordance with the written commitment and recording
    of the results
  5. A final validation report with all available data, duly approved by higher management,
    declaring whether or not the process has been successfully validated.[/color][/b][b]

Health Canada’s Objectives:[/b]
1. One should verify the effectiveness of the cleaning procedure for removal of product
residues, degradation products, preservatives, excipients, and/or cleaning agents
so that analytical monitoring may be reduced to a minimum in the routine phase.
2. Cleaning procedures must strictly follow carefully established and validated
methods.
3. Appropriate cleaning procedures must be developed for all product-contact equipment
used in the production process. Consideration should also be given to noncontact
parts into which product may migrate (e.g., seals, fl anges, mixing shaft,
fans of ovens, heating elements, etc.).
4. Relevant process equipment cleaning validation methods are required for biological
drugs because of their inherent characteristics (proteins are sticky by nature),
parenteral product purity requirements, the complexity of equipment, and the
broad spectrum of materials that need to be cleaned.
5. Cleaning procedures for products and processes that are very similar do not need to
be individually validated. This could be dependent on what is common, equipment
and surface area, or an environment involving all product-contact equipment.

[b][COLOR=“blue”]EU Guidelines & Expectations:

  1. Cleaning validation should be performed in order to confi rm the effectiveness of
    a cleaning procedure. The rationale for selecting limits of carryover of product
    residues, cleaning agents, and microbial contamination should be logically based
    on the materials involved. The limits should be achievable and verifi able.

  2. Validated analytical methods with the sensitivity to detect residues or contaminants
    should be used.

  3. The detection limit for each analytical method should be suffi ciently sensitive to
    detect the established acceptable level of the residue or contaminant.

  4. Normally only cleaning procedures for product-contact surfaces of the equipment
    need to be validated. Consideration should be given to no contact parts. The
    intervals between use and cleaning as well as cleaning and reuse should be
    validated. Cleaning intervals and methods should be determined.

  5. For cleaning procedures for products and processes, which are similar, it is
    considered acceptable to select a representative range of similar products and
    processes. A single validation study utilizing a “worst-case” approach can be
    carried out, which takes account of critical issues.[/color][/b]

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

Thank you Mr. Durga Prasad for your guidance, this is valuable for me.

can you provide me web link for mentioned guidelines (i.e. USFDA, MHRA, EU-GMP, Health Canada, WHO Geneva, ANVISA).

Regards,
ANIL SAXENA

[quote=DURGA PRASAD]Mr.Saxena,
Its very difficult to get a Unauthorized PDA Technical Report 29. And its illegal.
Best thing is that ask your company to become a member in PDA by paying membership fees of 150 to 250$/Year and they can purchase this report or your company can purchase this by paying 150$ directly from PDA Site by downloading that document

I can mention here what FDA & Regulating agencies expect about Cleaning validation:

[b][COLOR=“darkred”]FDA, in its guidelines for cleaning validation, has clearly expressed expectations that
industries have to fulfill. The basic requirements, as per FDA, are as follows:

  1. A written procedure on how cleaning processes will be validated
  2. Clearly outlined responsibility for performing and approving validation study,
    acceptance criteria, and revalidation requirement
  3. Approved written protocols describing the study to be performed, system or piece
    of equipment, sampling procedures, testing methods, and so on
  4. Execution of the protocols in accordance with the written commitment and recording
    of the results
  5. A final validation report with all available data, duly approved by higher management,
    declaring whether or not the process has been successfully validated.[/color][/b][b]

Health Canada’s Objectives:[/b]
1. One should verify the effectiveness of the cleaning procedure for removal of product
residues, degradation products, preservatives, excipients, and/or cleaning agents
so that analytical monitoring may be reduced to a minimum in the routine phase.
2. Cleaning procedures must strictly follow carefully established and validated
methods.
3. Appropriate cleaning procedures must be developed for all product-contact equipment
used in the production process. Consideration should also be given to noncontact
parts into which product may migrate (e.g., seals, fl anges, mixing shaft,
fans of ovens, heating elements, etc.).
4. Relevant process equipment cleaning validation methods are required for biological
drugs because of their inherent characteristics (proteins are sticky by nature),
parenteral product purity requirements, the complexity of equipment, and the
broad spectrum of materials that need to be cleaned.
5. Cleaning procedures for products and processes that are very similar do not need to
be individually validated. This could be dependent on what is common, equipment
and surface area, or an environment involving all product-contact equipment.

[b][COLOR=“blue”]EU Guidelines & Expectations:

  1. Cleaning validation should be performed in order to confi rm the effectiveness of
    a cleaning procedure. The rationale for selecting limits of carryover of product
    residues, cleaning agents, and microbial contamination should be logically based
    on the materials involved. The limits should be achievable and verifi able.

  2. Validated analytical methods with the sensitivity to detect residues or contaminants
    should be used.

  3. The detection limit for each analytical method should be suffi ciently sensitive to
    detect the established acceptable level of the residue or contaminant.

  4. Normally only cleaning procedures for product-contact surfaces of the equipment
    need to be validated. Consideration should be given to no contact parts. The
    intervals between use and cleaning as well as cleaning and reuse should be
    validated. Cleaning intervals and methods should be determined.

  5. For cleaning procedures for products and processes, which are similar, it is
    considered acceptable to select a representative range of similar products and
    processes. A single validation study utilizing a “worst-case” approach can be
    carried out, which takes account of critical issues.[/color][/b]

6. Typically, three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.[/quote]

Hi,

Here are some links. But these are only guidelines and not explaination.

Health Canada:

http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/validation/gui-0028_cleaning-nettoyage_ltr-doc-eng.php

FDA:

MHRA / EU (includes Cleaning validation):

http://tern-quay.com/Orange_Guide/Annexs/EU-GMP-Vol4_Annex15b.pdf

Regards,

Thank you very much Mr. Shoaib for links provided by you.

two more question related to MACO Calculation

  1. we add new product in product matrix & if worst case product is not changed then MACO limit for new product is to be worst case limit or new calculated limit (this may be lower or higher than worst case limit) ?
    because we have procedure for cleaning verification study for other than worst case product.

  2. During MACO calculation for new product formula is

MACO = TD x BS x SF x Swab Area / LDD x Total Equipment surface area

TD = Minimum Therapeutic Dose of product A (i.e. new product minimum dose)
BS = Minimum Batch size of product B (from product matrix)
SF = Safety Factor
LDD = Largest Daily Dose of product B (from product matrix)

At the time of new product addition, if worst case product is not changed, then during MACO Calculation as per above formula Product B is WORST CASE PRODUCT OR we select minimum batch size & LDD from matrix that may be differ from worst case product BS & LDD ?

Pls. reply me point wise.

Thanks in advance

Anil Saxena

Hi Anil,

Apologies for the late reply, I did not login to the forum last week.

Answer to Q1) MACO limit would be new calculated limit, might be higher or lower.

Q2) You’ll select BS and LDD that may differ from worst product.

Any new product introduced in the matrix or equipment train may have an effect on the limit calculations depending on the product mfg specs.

Regards,

Hi Mr. Shoaib,

Cleaning Validation is a vast area which have many doubts or questions.

so, i have one more question
During MACO calculation for worst case product, MACO is lower than LOD or LOQ value. In that case which limit we select for worst case product. LOD is 0.05 ppm.

see attachment.

Regards,
ANIL SAXENA


MACO.doc (52.5 KB)

Hi Anil,

In this case, we should go for the 1/1000th or 10 ppm limit.

However to be honest, since cleaning validation is not my “area of expertise”, I would recommend you to further consult on this matter.

Other forum members are welcome to provide their valuable suggestions. If I find a more suitable answer to your question, I’ll get back to you ASAP.

Regards,

Dear Shoaib

you can go with general limit calculation [10 ppm criteria]

In the APIC guideline general limit chapter explains as follows:

“If the calculation methods based on therapeutic doses or toxicological data result in unacceptably high or irrelevant carryover figures, or toxicological data for intermediates are not known, the approach of a general limit may be suitable”.

Thanks

Prasad

Dear Mr. Durga Prasad,

Can u pl. tell me, how to establish a Campaign Period for manufacturing a oral solid product, can it be exceeded more than the established Dirty Equipment Hold Time period, as of now i have established dirty equipment hold time study of 72 hrs. and want to establish the campaign period for tablet manufacturing including granulation and compression of 6 days.

Regards,

Ranjit

This “dirty” hold time has to be be determined based on the material attributes or properties of various materials you use in your production during campaign production schedules. The cleanability and degradation time schedules varie and change for different products.

All you need in your case is to find a “WORST CASE” which is based on the cleanability lapse time period or limit so that all the pre-requisites are met.

There is a no defined regulatory guidance on this subject as the products change from facility to facility and campaign periods.

Here are 2 questions about clean validation in campaign production, which need help and comments:

  1. Is simple or minor clean acceptable within campaign production?

  2. Is PV necessary for a Campaign batch?

Thanks very much for your kind help!

Cleaning should be complete. Tested and Proved.
Process Validation is a must.

Dear Mr. Durga,

Please advice following conditions,

  1. Is material dedicated equipment needs to conduct cleaning validation for example Liquid Glucose storage tank, Sugar hopper?
  2. As materials are favorable to microbial growth is it sufficient to demonstrate dirty holding time with reference to microbiological testing?
  3. Please advice in case of campaign manufacturing, can we demonstrate microbial control through dry swab sampling till maximum limit time?

Looking forward for your expert opinion.