SOP OF CORRECTIVE AND PREVENTIVE ACTIONS (CAPA)

1.0 OBJECTIVE:

To lay down the procedure for to be followed for administration of Corrective and Preventive actions (CAPA) including tracking and reporting of the status of CAPA.
2.0 SCOPE:
This SOP shall be applicable for track and follow up open CAPA as well as verification of completed CAPA.
Corrective action:
Action taken to rectify, fix or correct a specific deviation, defect or undesirable situation.
Preventive action:
Action taken to eliminate the cause of deviation, defect, or other undesirable situation in order to prevent the future occurrence of such or similar an event.
Source documents of CAPA are identified as:

• GMP Investigations
• Deviations
• Laboratory (OOS) Investigations
• Internal Audit Reports
• External / Customer Audits
• Annual Product Reviews
• Regulatory Inspection Reports
• Management Action Plans
• Changes in regulatory / Pharmacopoeia requirements 
• Product Failures
• Complaints
• Product recall
• Returned Goods
• Incidence Reports
• Discrepancies

3.0 RESPONSIBILITY:
All Department Heads

4.0 ACCOUNTABILITY:

Head Quality Assurance

5.0 PROCEDURE:
5.1 Source document shall provide the proposed corrective and preventive actions. The proposed corrective and preventive actions shall be approved by QA prior to implementation. The proposed corrective and preventive actions shall be verified during CAPA evaluation in form.
5.2 The "CAPA" form shall be treated as a tracking form of Corrective and Preventive actions from source document.

5.3 Initiation of CAPA:

5.3.1 Department Head shall decide the need for CAPA during initiation of any source document mentioned in Scope.
5.3.2 The Department Head shall get a CAPA form issued from QA. QA shall write the source document name and Source document number on the form before issue of form. Record of CAPA form issued shall be maintained by QA.
5.3.3 Department Head shall fill the CAPA form as under.
5.3.3.1 Write the name of the department
5.3.3.2 Date CAPA initiated
5.3.3.3 Proposed completion date
5.3.4 Carry out root cause analysis and write description based on the source document.
5.3.5 Write in brief the CAPA description from the source document and corrective and preventive action details.
5.3.6 The Department Head shall write their name with signature and date.
5.3.7 The department head shall send the CAPA form to QA.
5.3.8 GM QA / Designee shall allot a reference number to the CAPA form and make relevant entries in the CAPA log. Forward the CAPA form to the concerned department.
5.3.9 The CAPA shall be numbered serially in the calendar year for each department with an identification code of department. A typical CAPA form shall be numbered as
CAPA/XXX/YYY/Z
Where,
XXX: department code.
YYY: serial number, commencing at 001 for each department in calendar year.
Z: Last two digits of a calendar year.
e.g. CAPA/PRD/007/15 represents the 7th CAPA from production department in calendar year 2015

DEPARTMENT CODES

QAD - Quality Assurance Dept.
QCD - Quality Control Dept.
PRD - Production Dept.
WHD - Ware House Dept.
ENG - Engineering Dept. 

HRD - Human Resource Dept. 

PKD - Packaging development Dept.
EHS - Environment Health & Safety Dept.

5.4 CAPA Closure and Verification:

5.4.1 On completion of actions, the department head shall certify that the proposed CAPA is completed and implemented along with associated actions.
5.4.2 QA shall verify the implementation and completion of CAPA with review of supporting documents and certify the same.
5.5 Any change proposed as a result of CAPA shall be through the SOP on Change Control. Reference of the same shall be mentioned in the CAPA format.
5.6 All Deviations, Discrepancy reports giving rise to CAPA shall be addressed through CAPA form.
5.7 All facility up-gradations / Capital purchase requirements / major changes in quality system for compliance to regulatory commitments giving rise to CAPA shall be addressed through CAPA form.
5.8 The record of each CAPA shall be maintained.
Copy of the completed CAPA shall be provided to the concerned Dept. Head by QA. A copy of CAPA form shall be attached to the source document.
5.9 Department Head shall compile the CAPA information and submit the summary to the Management during GMP Committee meeting / Management Review Meeting.
5.10 Management shall review / verify the same quarterly in Management Review Meeting.
5.11 Information and documents related to CAPA drawn form internal audits, external/ Customer audits and regulatory inspections are considered confidential and can only be made available to regulatory review when approved by Director Technical and Sr. Vice President.

6.0 ABBREVIATIONS:

6.1 SOP: Standard Operating Procedure

6.2 CAPA: Corrective Action and Preventive Action

6.3 GMP: Good Manufacturing Practices

6.4 OOS: Out of Specification

6.5 GM: General Manager

                                                     ANNEXURE-1

                                              Request form for CAPA

Originating Department Name		Date
Request No.
Present Process / Problem :
Proposed Action (If any ):
Acceptance Criteria of proposed action :
Approval by Head of Originating Department :                                                                                                                Signature/Date

                                                       ANNEXURE-2

                FORMAT FOR CORRECTIVE AND PREVENTIVE ACTION

Department Name :-                                                         Report No. Ref. request No.(if any):-
Description :
Corrective action:-	Target date of completion	Completion Date
Preventive Action :-
Acceptance Criteria :-
Approval:- Head Originating department                                                   Head Quality Assurance (Sign./Date)                                                                                (Sign./Date)
Implementation and Follow up  verified by Originating department                                                                 Quality Assurance (Sign./Date)                                                                                    (Sign./Date)

SOP OF PROCEDURE OF FUMIGATION IN PRODUCTION AREA

1.0  OBJECTIVE:

       To lay down the procedure of fumigation in production area by using 5 % Gramicid and Fogger.

2.0  SCOPE:

       This SOP shall be applicable for all the area of Production.

3.0  RESPONSIBILITY:

3.1  Execution              : Operator

3.2  Checking               : Production Pharmacist & Above

4.0  ACCOUNTABILITY:

       HOD-Production / Assigned Designee

5.0  PROCEDURE:

5.1  Fumigation should be carried out at the end of the production operation twice in a month and whenever required.

5.2  Production person shall ensure that raw Material, finished goods, intermediates or in process goods should not be present in area of Fumigation. If present cover all the materials with polythene bags.

5.3  Always use nose-mask and Goggles while doing fumigation as Gramicid is irritating to human eye.

5.4  Windows, doors should be closed; AHU’s should be switched off before starting fumigation.

5.5  Place 5% Gramicid in the fogger and switch “ON” the fogger.

5.6  After fumigation of area is complete, Switch “OFF” the fogger and affixed the label as “Area under fumigation, do not enter” on every side   of the entrance. Allow the fumigation fumes to stay for about 6-7 hrs.

5.7  After the specified time of fumigation is over, enter the area only by starting exhaust for about 30 minutes.

5.8  Conduct cleaning before processing any product in the concerned area.

5.9  After 30 minutes, start the AHU’s allow to stabilize to attend required temperature and humidity then start the routine production operation.

5.10  Fill the “Fumigation Record”.

6.0  ABBREVIATIONS:

6.1  SOP: Standard Operating Procedure

6.2  Q.A.: Quality Assurance

6.3  HOD: Head of The Department

DRUG MASTER FILE (DMF)

DRUG MASTER FILE (DMF)

Drug Master File (DMF) : is a document prepaired by a pharmaceutical manufacturer and submittedsolely at its discretion to the appropriate regulatory agency.DMF contains confidential and factual information about facilities, processes(includes drug product's chemistry, manufacture, stability, purity, impurity profile etc.) or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.DMF helps the manufacturer to keep relevant information secret and at the same time to sell the product to different customers using this drug within there final application.The information contained in the DMF may be used to support an Investigational New Drug Application (IND), a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA), A DMF is NOT a substitute for an IND, NDA, ANDA, or Export Application. It is not approved or disapproved. Technical contents of a DMF are reviewed only in connection with the review of an IND, NDA, ANDA, or an Export Application.

DMF contains complete information on an Active Pharmaceutical Ingredient (API) or finished drug dosage form. In Europe it is known as European Drug Master File (EDMF) or Active Substance Master File (ASMF) and in US it is known as US-Drug Master file (US-DMF).


DMF’s are mostly prepared following the rules of Common Technical Documentation (CTD).

Prerequisites

Production process is well established and fixed in writing (Master production instructions).
Specifications of raw materials as well as of the final product are defined including specification of packaging material.
Inprocess controls, sampling points and procedures are clearly outlined.
Critical process steps are validated, equipment is qualified.
Analytical methods are validated.
Impurity profile is established.
Stability program is set up and first data are available.
Basic GMP requirements are fullfilled.

Data required for the CTD are

General Information
Nomenclature
Structure Description
General Properties
Manufacture
Manufacturer(s)
Description of manufacturing process and process controls
Control of materials
Controls of critical steps and intermediates
Process validation and/or evaluation
Manufacturing process development.
Characterisation
Elucidation of structure and other characteristics
Impurities
Control of drug substance
Specification
Analytical Procedures
Validation of analytical procedures
Batch analyses
Justification of Specification
Reference Standards or Materials
Container Closure System
Stability


US-DMF

In United states DMFs are submitted to the FDA.The main objective of the DMF is to support regulatory requirements and prove the quality,safety and efficacy of the medicinal product.

In US there are five types of DMF's:
Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel

Type II Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product

Type III Packaging Material

Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation

Type V FDA Accepted Reference Information

Type I
 Manufacturing Site, Facilities, Operating Procedures, and PersonnelA Type I DMF is recommended for a person outside of the United States to assist FDA in conducting on site inspections of their manufacturing facilities. The DMF should describe the manufacturing site, equipment capabilities, and operational layout.

The description of the site should include acreage, actual site address, and a map showing its location with respect to the nearest city. An aerial photograph and a diagram of the site may be helpful.

A diagram of major production and processing areas is helpful for understanding the operational layout. Major equipment should be described in terms of capabilities, application, and location. Make and model would not normally be needed unless the equipment is new or unique.

A diagram of major corporate organizational elements, with key manufacturing, quality control, and quality assurance positions highlighted, at both the manufacturing site and corporate headquarters, is also helpful.

　

Type II

Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug ProductA Type II DMF should, in general, be limited to a single drug intermediate, drug substance, drug product, or type of material used in their preparation.It Summarize all significant steps in the manufacturing and controls of the drug intermediate or substance.

Type III

Packaging MaterialEach packaging material should be identified by the intended use, components, composition, and controls for its release. The names of the suppliers or fabricators of the components used in preparing the packaging material and the acceptance specifications should also be given. Data supporting the acceptability of the packaging material for its intended use should also be submitted.

Type IV

 Excipient, Colorant, Flavor, Essence, or Material Used in Their PreparationEach additive should be identified and characterized by its method of manufacture, release specifications, and testing methods.

Toxicological data on these materials would be included under this type of DMF, if not otherwise available by cross reference to another document.

Type V

FDA Accepted Reference InformationFDA discourages the use of Type V DMF's for miscellaneous information, duplicate information, or information that should be included in one of the other types of DMF's. If any holder wishes to submit information and supporting data in a DMF that is not covered by Types I through IV, a holder must first submit a letter of intent to the Drug Master File Staff (for address, see D.5.a. of this section). FDA will then contact the holder to discuss the proposed submission.

General Requirements for Filling Type I,II,III,IV,V DMF's
Type II, Type III, and Type IV DMF's should contain a commitment by the firm that its facilities will be operated in compliance with applicable environmental laws.

Stability study design, data, interpretation, and other information should be submitted.

A DMF is required to contain a complete list of persons authorized to incorporate information in the DMF by reference.

EDMF

In Europe DMFs are submitted to EMEA. The main objective of the Active Substance Master File (ASMF) procedure, commonly known as the European Drug Master File (EDMF), is to allow valuable confidential intellectual property or 'know-how' of the manufacturer of the active substance (ASM) to be protected, while at the same time allowing the Applicant or marketing authorisation (MA) holder to take full responsibility for the medicinal product and the quality and quality control of the active substance. Competent Authorities/EMEA thus have access to the complete information that is necessary for an evaluation of the suitability of the use of the active substance in the medicinal product.

The scientific information in the EDMF should be physically divided into two separate parts, namely the Applicants Part (AP) and the Restricted Part (RP). The AP contains the information that the EDMF holder regards as non-confidential to the Applicant/MA holder, whereas the RP contains the information that the EDMF holder regards as confidential.

It is emphasized that the AP is still a confidential document that cannot be submitted by anyone to third parties without the written consent of the EDMF holder. In all cases the AP should contain sufficient information to enable the Applicant/MA holder to take full responsibility for an evaluation of the suitability of the specifications for the active substance to control the quality of this active substance for use in the manufacture of a specified medicinal product. The RP may contain the remaining information, such as detailed information on the individual steps of the manufacturing method (reaction conditions, temperature, validation and evaluation data of critical steps) and the quality control during the manufacture method of the active substance.

The EDMF procedure can be used for the following active substances (except biological active substances)

A. New active substances

B. Existing active substances not included in the European Pharmacopoeia (Ph. Eur.) or the pharmacopoeia of an EU Member State

C. Pharmacopoeial active substances included in the Ph. Eur. or in the pharmacopoeia of an EU Member State

DMF (Drug Master File), CoS (Certificate of suitability) as well as CMC (Chemical Manufacturing and Control Documentation) are used for one and the same intention – to give evidence, that the drug substance (API – Active Pharmaceutical Ingredient) is suitable for its intended use and that the manufacturing process is well established and controlled. Content of DMF, CoS, and CMC are nearly equal. There are only differences in the kind of document preparation (forms to use) and the authority you have to contact (USDMF FDA; EDMF EMEA; CoS EDQM; CMC national bodies). Therefore above mentioned procedure is nearly equal for all the three types. Especially CoS does not replace an approval process. Approval authorities can require more information even if CoS is available.