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Cleaning validation protocol_2

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					Sample cleaning validation
protocol Aravindsai
(www.pharmacygraduates.org




                                  Cleaning
                             Validation
                             Protocol




    For formulation and filling
    Supervised and controlled by
    QA



                                        2010
                WRITTEN:             REVIEWED:
Signature:   Position: Validation manager Laboratory Manager Microbiology Manager
Date: 22/05/2010 23/05/2010 24/05/2010




   APPROVED


 Signature:
 Position: QA Manager Engineering Manager Production Manager
 Date:    24/05/2010 24/05/2010 24/05/2010
                             Table of
                            Contents


 1. OBJECTIVE



 2. SCOPE

 3. RESPONSIBILITY AND AUTHORITY


 4. REFERENCED DOCUMENTS


 5. REVIEW OF CLEANING
 PROCEDURES
 5.1 Equipment to be
cleaned

     5.2 Possible residues
     5.3 Cleaning procedure(s) and cleaning
     equipment
     5.4 Holding times

6. SELECTION OF WORST CASE
 6.1 Evaluation of the Product Mix to select the worst-case product
“MARKER” OR “WORST CASE”
or marker product 6.2 Operator training
PRODUCT
6.3 Cleaning limits selection criteria based on MAC
approach

7. VALIDATION PLAN
 7.1 Worst-case
conditions
      7.2 Chemical and microbiological
      analytical methods 7.3 Acceptance
      criteria

8. SAMPLING LOCATIONS

      8.1 Swab and flush sampling
8.2 Sampling method
      locations


13. REQUIRED DOCUMENT
1. OBJECTIVE

The objective of this protocol is to define approach to the validation
of cleaning procedures for formulation and filling

2. SCOPE
This document covers the protocols
of cleaning validation for
formulation and filling equpments
3. RESPONSIBILITY AND AUTHORITY


Validation unit Production Engineering              R&D
                                                 QAdevelopment QC
Analytical


   Preparation     Approve       Assist     Approvi    Developin    Perform
   of protocol     validati      in         n g        g            recover
                   on
                   plan and      identif
                                 g hard     protocol   analytic     studie
                   working       yinclean
                                 to         s          al           s
                   plan          areas                 method



   Calculate       Verifyin       Oversee the           Testing samples
   contaminatio    g             process               and preparin
   n limits for    accuracy
                   of
   active          cleaning
   ingredient      procedur                                         g
   and cleaning    e                                                analytic
   agent                                                            al
                                                                    report


   Conduct         Identif        Approvin g report
   validation      yin g
                   hard to
   including
                   clean
   sampling        areas


   Preparing       Performin g cleaning
   validation
   report
4. REFERENCED DOCUMENTS




5. REVIEW OF CLEANING PROCEDURES

    5.1 Equipment’s

       
       
       Mixing
        Vial
       vesselsFilling and closing machine Equipment Criticality
       Transfe
       r pipesRationale Mixing vessel Critical Direct contact with
       rating
       the product Vial filling and closing


         machine Critical Direct contact with the product

         Labelling machine Non-critical for      Doesn’t
         cleaning                                purity
                                                 affect of the
                                                 drug
                                                 quality
                                                 substance
          (no direct contact) Cartonator Non-critical for cleaning
                                                 and
          Doesn’t affect quality and
                                                 purity of the
                                                 drug
          (no direct contact) Freeze dryer Non-critical for cleaning
                                                 substance
          Doesn’t affect quality and
                                                 purity of the
                                                 drug
                                                 substance
          (no direct contact) Rotary table Non-critical for cleaning
          Doesn’t affect quality and
                                                 purity of the
                                                 drug
          (no direct contact) Coveyor Non-critical for cleaning
                                                 substance
          Doesn’t affect quality and
                                                 purity of the
                                                 drug substance
                                                 (no direct
     Hard to clean                               contact)
    areas:
       
        Dead
       Beneath
     Dead legs
       the
       spots
       mixing
       in the
       blades
       tank
     5.2 Potential residues
         By products or degradation
         Previous Active
        products ofproduct pharmaceutical
         Microbes
        ingredients
         Solvents or chemicals used
      Cleaningmanufacturing
        during agents and lubricants used for
     cleaning 5.3 Cleaning procedure(s) and
     cleaning equipmentClean in place
     Cleaning method:
         Pre-wash: Use tap water to clean
         Clean applying cleaning
        the parts of equipment. solution
         the pre-washed parts.
        toBlow out using compressed air
         Rinse the Equipment parts using
         Again rinse it with purified
        tap water
 Dry using hot and compressed air.
        water
Cleaning Agents: Water and
 5.4 Holding
hypochlorite times


         Pre-washing or pre-rinsing 10
         Washing 30 minutes
        minutes
         Rinsing 10 minutes
 Drying 10 minutes


6. SELECTION OF WORST CASE
   6.1 Evaluation of the Product Mix to select the worst-case product
“MARKER” OR “WORST CASE”
or marker product
PRODUCT

Doses and Batch Size Information


Product Strength Solubility Toxicity Batch
                                                          Size Decision**

FCP 50mg C&C Liquid 50mg High High 50 kg FCP 75mg C&C Liquid 75 mg
High Low 100 kg Bracket FCP 100mg C&C Liquid 100 mg High Low 100
kg Marker FCP 250mg C&C Oily Liquid 250 mg Low Medium 25 kg Bracket
FCP X Strength C&C 1000 mg




                                         Medium High 150 kg Ma

FCP 100mg C&C Liquid 100mg Low High 100 kg Marker
FCP 100mg C&C Liquid is marker as its solubility is low and toxicity
is high ,since as it is of more batch size, they possibility of residue
will be more. Hence if it can be cleaned without toxic residue the rest
all can be cleaned.
6.2 Operator training Operator performing the cleaning programme
should be trained and assessed before they start
the cleaning process. Records of their
training and assessment should be preserved.


6.3 Cleaning limits selection criteria based on MAC
approach Maximum allowable carryover (ppm) =


Maximum allowed concentration from previous batch x minimum batch
size of next product

7. VALIDATION PLAN

The worst-case conditions are as follows:

Products having high toxicity and low solubility should be considered
as marker because if they can be cleaned without any toxic residue
all the others can be cleaned
High toxicity and low solubility=FCP 100mg
C&C Liquid High toxicity and medium
solubility= FCP X Strength C&C
Medium toxicity and Low solubility =FCP 250mg C&C
Oily Liquid 7.2 Chemical and microbiological
analytical methods
 For detecting the chemical residues HPLC is used and for detecting
microbial contamination

Analyte Method Protein HPLC



Organic compounds HPLC

Inorganic compounds Conductivity of rinse water



 For detecting microbial
contamination
 Viruses Bacteria Parasitic protozoa Method for detecting Cell culture and
count
                    plaque forming units Selective            Immunological
                    growth on agar and count colony staining and
                    forming units                             count
                                                              fluorescent
 7.3 Acceptance                                               cysts
criteria

For chemicals: 1. Not more than 0.1% of the normal therapeutic dose
of any product to appear in the maximum
daily dose of the following product; 2. Not more
than 10 ppm of any product to appear in another
product
3. No residue of hypochlorite (cleaning agent)
should be identified
                   For
microbes (USP)

Medium used Total     Total    Staphylococcus aureus Pseudomonas aeruginosa
aerobic count         yeast    E.coli Salmonella
                      and
                      mold
                      count

Alginic acid Not         Should not be present                      Should
more than 200 total                                                 not be
bacterial                                                           present

            co
            un
Benzalkoniu t Should not be present
m chloride
(<5%)

Sugar spheres 100 Should not be                         present Should
                                             Should not be
present
be present Lactose                                      not
                                             present Should not
                                             be

monohydrate 100 50      Should not be present                       Should
                                                                    not be
                                                                    present
8 SAMPLING LOCATIONS

     8.1 Swab and flush sampling locations
     (For tank)

             Swab
                          Swab Location (100 square cm area)
             Number
               S1 Under mixing tank lid S2
               Right side wall surface
               S3 Under the mixing blade
               S4 Valves S5 Pipes

     Flush
             Number 1000 mL of final flush purified water
               F1 Drain line from Bulk Tank
               Swab and flush sampling locations
     (for filling equipment)

            Swab Number Swab Location (100 square cm
            area) S6 Filling head
 Flush Number 1000 mL of final flush purified water


F2 Drain Line from Filler


     8.1 Sampling method

   Pre-treat the swab in the solvent and squeeze it

   Swab in the mixing vessel with one side in horizontal direction
  and other side in the vertical direction, back and forth to cover
  the entire area (in the locations mentioned above)

   Cut off the handle of swab into centrifuged tube

    Use recovery solvent to extract drug residue by
   sonication
 The filtered extract is analyzed
through HPLC

				
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