Guideline :

Health Products and Food Branch Inspectorate  Cleaning Validation Guideline-   Health Canada.

Definition:

Cleaning Validation:

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

Types of contaminants

• Chemical – Residues of the previous product
• Biological – Microorganisms
• Physical    – Particulate matter

Solubility of API shall be mentioned as per following Table:

Solubility	Approximate volume of solvent in milliliters per gram of solute
Very soluble	Less than 1 part (< 1)
Freely soluble	From 1 to 10 parts (1 : 10)
Soluble	From 10 to 30 parts (10 : 30)
Sparingly soluble	From 30 to 100 parts (30 : 100)
Slightly soluble	From 100 to 1000 parts (100 : 1000)
Very slightly soluble	From 1000 to 10000 parts (1000 : 10000)
Practically insoluble	More than 10000 parts (> 10000)

LD50 of API shall be mentioned as per following Table:

Probable oral Lethal dose for humans (Mg/ kg)	Included descriptive terms
>15000	Practically non toxic
5000-15000	Slightly toxic
500-5000	Moderately toxic
50-500	Very toxic
5-50	Extremely toxic
<5	Super toxic

Cleanability of API shall be mentioned as per following Table:

Solubility	Approximate volume of solvent in milliliters per gram of solute	Cleanability Index
Very soluble	Less than 1 part (< 1)	Easily cleanable
Freely soluble	From 1 to 10 parts (1 : 10)	Easily cleanable
Soluble	From 10 to 30 parts (10 : 30)	Easily cleanable
Sparingly soluble	From 30 to 100 parts (30 : 100)	Hard to clean
Slightly soluble	From 100 to 1000 parts (100 : 1000)	Hard to clean
Very slightly soluble	From 1000 to 10000 parts (1000 : 10000)	Mechanical water forced required
Practically insoluble	More than 10000 parts (> 10000)	Mechanical water forced required

All equipments parts shall be identified as per rational criteria and categories as per bellow

• Hard to clean
• Direct contact with product
• No direct contact with product

Sampling Techniques :

Visual Inspection (Method For Validation of Cleaning of Equipments):

After cleaning of the equipment visual inspection shall be done using a torch held inclined to the  surface being inspected, and a mirror (attached to stainless steel rod) to inspect the surface of  equipment. Visual inspection shall be done by unaided naked eye.

For visual cleaning;

Verify the cleanliness of the product contact surfaces. Verify the cleanliness of hard to clean areas.

Verify all the product contact dismantled parts before and after assembling.

Surface Swab Sampling:

The direct Sampling technique is also commonly referred to as “Direct Surface Sampling” method.   This is done by Swabbing Technique using Swabs. The direct surface sampling method is the preferred technique.

Sampling Procedure:

Surface sampling is identified as a sampling method considering the design, size and number of equipment.

After the completion of equipment cleaning, visual inspection shall be done.

In case, the surface of equipment is difficult to inspect, a mirror attached to a stick shall be used to inspect the cleanliness of equipment.

Complete product contact surface area shall be sampled for critical hard to clean area/ critical accessories like spray gun, punch, dies, and butter fly valve etc.

Swab Sampling for Chemical analysis:

After visual inspection is found satisfactory swab sampling shall be carried out. Wear hand gloves and nose mask before commencing swab sampling.

The swab must be wetted in purified water or suitable diluents.

Swab area shall be measured with the help of template for swabbing and  the area must be 5cm x 5cm  or as per protocol.

Swabbing shall be done by parallel horizontal and then tilt the swab and do vertical strokes  as  described below to assure that the entire area is swabbed.

After swabbing, place the swab into a stoppered test tube, wrap with aluminum foil and label the test tube for identification of swab sample.

Swab samples must be collected from different areas of equipment as stated in the cleaning validation protocol.

Send the stoppered test tube with swab to Quality Control Laboratory for analysis.

Swab sampling for Microbial analysis:

Wear sterile hand gloves and nose mask before commencing swab sampling to avoid the microbiological contamination. Sterile cotton swab shall be used for swabbing.

The sterile cotton swab shall be soaked in sterile saline.

Swabbing shall be done by parallel horizontal and then tilt the swab and do vertical  strokes  as  described below to assure that the entire area is swabbed.

Swab area shall be measured for swabbing and the area must be 5cm x 6cm.

Microbial swab sample shall be collected before chemical swab.

Swabbing shall be done on the surface of equipments and the area is different from the area of swab taken for chemical analysis.

After swabbing, place the swab into a sterilized stoppered test tube and label the test tube for identification of swab sample.

Swab samples must be collected from different areas of equipment as stated in the cleaning validation protocol.

Send the sterile stoppered test tube with swab to Quality Control – Microbiology Laboratory for analysis.

Rinse Sampling Procedure:

After visual inspection is found satisfactory, the equipment shall be rinsed with the volume of rinsing solvent (purified water) as described in respective cleaning validation protocol (rinse sample shall be performed whenever necessary).

Rinse sample shall be collected in the bottles used for the collection of routine purified water samples.

After the collection of rinse sample, (stopper) close the bottle and label it for identification of rinse sample. Send the rinse sample bottle to Quality Control Laboratory for analysis.

Product Container Lid for Example

Method of analysis:

Methods of analysis used for determination of possible contaminant residues must be specific and sensitive.

The selection of analytical methods shall be validated for at least below  mentioned parameters based  on at least the following but not limited to;

• Precision,
• Specificity
• Linearity and Range,
• Limit of Detection,
• Limit of Quantification,
• Stability of solutions,
• Recovery from Equipment Surface.

FOR WORST CASE APPROACH;

10 PPM Criteria:

MACO =[Mac10] x [Swab Area]/[Shared equipment surface area between products]

Where,

Mac10     = 10 ppm x Minimum Batch Size of Product ‘B’ in kg.

Dose Criteria :

ACCEPTABILITY LIMITS:

Visual inspection criteria:

No quantity of residue should be visible to naked eyes on the equipment after cleaning procedures are performed (i.e. less than 100 mcg /25 cm²).

10ppm criteria: Not more than 10ppm of active pharmaceutical ingredient of previous product is permitted in next product.

Dose based criteria:

Not more than 1/1000 of minimum daily therapeutic dose of  the  previous  product in the maximum daily dose of the next product The acceptability limits for microbiological sample shall be determined based on;

Parameters	Limit Dirty Equipment Surfaces	Limit Cleaned Equipment Surfaces
Total Aerobic Microbial Count (TAMC)	NMT 1000 cfu/swab	NMT 100 cfu/ swab
Total    Combined    Yeasts    and Molds Count (TYMC)	Less Than 10 cfu/swab	Less Than 10 cfu/ swab

Re-validation:

Re-validation shall be performed in case of any change, (at least the following but not limited to)

• Introduction of a new facility, equipment, process or product.
• Change in cleaning procedure.
• Change in cleaning agent used for cleaning.
• Reduction in minimum batch size and lowest dose of the product i.e change in  MACO  limit.
• Major Modification in processing equipment.
• Periodic revalidation after every three years.
• Change in regulatory requirements.

Dirty Equipment Hold Time (DEHT) –

The time from the end of manufacturing till the beginning of

the cleaning process of equipment (also called things like “soiled hold time”)

The Hold Time Study of Dirty Equipments shall be carried out by keeping equipment in idle for a  period of 24 hours in dirty condition. (The Maximum possible hold period under normal conditions) to evaluate microbial contamination on equipment surface and effectiveness of cleaning process.

Clean Equipment Hold Time (CEHT) –

The time from the end of equipment cleaning till subsequent use of equipment (subsequent use includes product manufacturing).

The Hold Time Study of Clean Equipments shall be carried out after completion of  “Type  B  Cleaning”, visual inspection by keeping equipment in idle clean condition up to 72 hours to establish  the expiry of cleaning in view of microbiology.

After the equipments surfaces are found visually clean, sampling and testing shall be carried out for Microbiological enumeration Tests and residual determination (chemical analysis) on the cleaned equipment surfaces at 0 hour interval, then sampling and testing shall be carried out only for Microbiological enumeration Tests at rest intervals as per the sampling plan. (i.e., after 24 hours, 48 hours and 72 hours).

Dirty Equipment Hold Time Period      : 24 Hours

Cleaned Equipment Hold Time Period : 48  Hours

Definition :

What is stability studies

The ability of a pharmaceutical product to retain its physical and chemical properties within specified limits throughout its shelf life.

Types of Stability Studies :

Long term testing

Stability studies under the recommended storage condition for the re-test period or shelf life proposed (or approved) for labeling.

Intermediate testing

Studies conducted at 30°C/65% RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substance or drug product intended to be stored long term at 25°C.

Accelerated testing

Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies. Data from these studies, in addition to long term stability studies, can be used to assess longer term chemical   effects at non-accelerated conditions and to evaluate the effect of short term excursions outside the label storage conditions such as might occur during shipping. Results from accelerated testing studies are not always predictive of physical changes.

Climatic zones The four zones in the world that are distinguished by their characteristic prevalent annual climatic conditions.

Climatic Zone No.	Definition	Storage Condition	Areas covered under the zone
I	Temperate climate	21°C & 45% RH.	United     Kingdom,      Northern                Europe, Canada, Russia, United states, Japan etc.
II	Subtropical and Mediterranean climate	25°C/60% RH	United   States,   Japan,  Southern Europe (Portugal-Greece) etc.
III	Hot & dry climate	30°C/35% RH	Australia, Argentina, Egypt, Iran, Iraq, Sudan, India etc.
IVA	Hot & humid climate	30°C/65%	Brazil,     Ghana,     Indonesia,               Nicaragua, Srilanka, Vietnam, Philippines, Uganda, Thailand, India etc.
IVB	Hot & very humid climate	30°C/75%	Brazil, Asian countries etc.

Factors affecting stability of the product

Temperature:

The rate of chemical reaction increases exponentially for each 10°C increase in temperature. This relationship has been observed for nearly all drug hydrolysis and some drug oxidation reaction.

Light:

Exposure to primarily, UV illumination may cause oxidation (photo oxidation) and scission (Photolysis) of covalent bonds.

Air:

Presence of oxygen, nitrogen.

Humidity (Moisture):

Esters & beta-lactoms are the chemical bonds that are most likely to hydrolyze in the presence of water.

E.g. the acetyl ester in aspirin is hydrolyzed to acetic acid and salicylic acid in the presence of moisture, but in a dry environment the hydrolysis of aspirin is negligible.

Selection of Batches

For new drug product, samples of at least three consecutive validation batches shall be kept for accelerated, Intermediate and long-term stability.

For routine stability study, one commercial batch shall be kept for long term stability on every year.

Testing frequency

Testing frequency shall be determined based on condition at which stability is performed.

Accelerated

Accelerated stability shall be conducted at 0, 3 and 6 months.

Long term

Long-term stability studies shall be carried out at the intervals of, Every three months on first year 0, 3, 6,9,12,

Every six months on second year 12, 18, 24

Every year thereafter through the proposed shelf life 24, 36, 48 and 60

Eg: 0, 3,6,9,12,18,24,36,48 and 60 months.

Intermediate Intermediate stability studies (minimum four time points, including initial and final points) shall be carried out at 0,3,6,9 and 12 months or up to 60 months.

Sampling for Stability Study

QA shall inform to QC regarding type of stability study to be performed. QC shall calculate the sample quantity and shall inform to QA.

Total sample quantity per batch shall be equivalent to 1.5 times of the quantity required for single complete or partial analysis & based on number of stations plus additional one station (since stability testing has to be continued for 12 month beyond the expiry).

Incubation of Stability Samples and Storage conditions

Samples shall be incubated as per below guideline.

Identify the storage conditions based on the Pharmacopoeial data or literature information or R&D information. For add on batch use long term storage conditions.

The long term testing shall cover a minimum of 12 months’ duration on at least three validation batches at the time of submission and shall be continued for a period of time sufficient to cover the proposed shelf life.

Long term, accelerated, and, where appropriate, intermediate storage conditions for drug products are detailed in the sections below.

Study	Storage condition	Minimum time period covered by data at submission
Long term	25°C ± 2°C / 60% RH ± 5% RH or 30°C ± 2°C / 65% RH ± 5% RH	12 months
Intermediate*	30°C ± 2°C / 65% RH ± 5% RH	6 months
Accelerated	40°C ± 2°C / 75% RH ± 5% RH	6 months

* If 30°C ± 2°C / 65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and “significant change” occurs at any time during 6 months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria.

The initial application should include a minimum of 6 months’ data from a 12-month study at the intermediate storage condition. Temperature & Humidity of stability incubator shall be monitored on daily basis. If incubation of the stability samples is delayed by 30 days or more from the release date of the batch, initial (0 month) analysis shall be performed again before incubation.

Analysis of the sample shall be performed on the due date or if not possible, then  complete within  below tolerance limit from due date.

Sr. No.	Stability Station	Tolerance (From due date of analysis)
1.	1M , 2M, 3M Accelerated, 3M long term, 3M Intermediate term	± 07 days
2.	6M Accelerated 6M, 9M, 12M long term. 6M, 9M, 12M Intermediate term.	± 15 days
3.	18M & onwards of long term.	± 30 days

If there is any out of trend result or failure to meet specification (significant change)  in  stability analysis, results shall be intimated to Head – QC.

Head – QC or designee shall investigate the out of trend (OOT) results according to the OOT SOP .

In case of Changes in the manufacturing process or site:

If minor changes done in the manufacturing process, Sample from batches produced under each change shall be added to stability program (one batch).

If major changes done in the manufacturing process, collect the samples from the new batches (three batches) and perform the stability like new product. In such a case the protocol and report procedure number shall be changed.

In case of manufacturing site change, evaluate the affect on stability of the drug product by keeping one batch for stability.

Stability guideline :

ICH guideline: ICH Q1A (R2)

Orange guide

DEFINATION:

New Vendor: Manufacturer identified by Formulation Development or purchase department as a manufacturer to supply of a specific material from a specific manufacturing site.

Approved Vendor: Manufacturer of raw material, primary and printed packaging material, which has been approved by QA to supply a specific material from specific site, based on the satisfactory cGMP history as well as compliance of material to specification.

PROCEDURE:

VENDOR DEVELOPMENT

The requirement of new raw & packing materials and their profiles shall be given by the formulations development department.

In charge-purchase (Vendor development) shall identify the vendors with the available  information based on specifications provided by formulations development department.

ASSESSMENT OF NEW VENDOR ( S) FOR NEW / EXISTING MATERIAL :

TEMPORARY APPROVED VENDORS

In order to select a new vendor, evaluation of the manufacturer’s capability, service performance and quality history is required. Purchase department shall collect and maintain information of the new  vendor through the vendor registration form for manufacturer and for supplier or Trade.

Purchase department will get technical information regarding the material through vendor questionnaire from the vendor which includes the brief manufacturing process, TSE/BSE free declaration, impurity profile, residual solvent information, GMO free declaration, Melamine free declaration, Gluten free declaration and stability data/shelf life statement etc. as applicable depending upon the type of material.

GMO : Genetically Modified Organism

Note: For non-critical excipients requirement of impurity profile, residual solvent information, stability data, GMO/Melamine/Gluten free declarations are not mandatory.

Purchase department shall ask the vendor for analytical method and analytical method  validation data for the materials claiming residual solvents. Based on the evaluation of above information and vendor registration form, Purchase/Formulation development department shall ensure that vendor is ready to supply material of required grade with specific requirement, if any.

Purchase department shall ask the vendor for pre-purchase samples of at least one batch depending    upon the along with its certificate of analysis and shall be sent to Formulation Development and/or Quality Control for analysis.

Formulation Development and/or Quality Control shall evaluate the source material lots and on compliance of the sample as per specification and shall confirm the suitability as per specification to purchase department.

Formulation Development and/Quality Control will intimate the purchase and QA for suitability of sample.

Based on the assessment report from Formulation Development and/Quality Control satisfactory evaluation of data provided by the vendor, the new vendor shall be considered as a ‘Temporary Approved’.

The vendor list contains Material Code, Material Name, Synonym/ Storage Condition, Manufacturer Name and Site Address, Suppliers Name and Address and current approval status. The vendor list shall be prepared, reviewed and approved. A separate vendor list shall be prepared for US/UK market and others.

Once vendor is temporary approved, vendor code is to be assigned to the particular vendor as well as material code in SAP is to be generated by purchase department in co-ordination with SAP department.

APPROVED VENDORS

Temporary approved” vendor becomes “Approved” vendor if following conditions are met-

For Manufacturer

Another Two commercial lots supplied by Temporary approved vendors are analysed and passed.

In case of API/ Primary packing material, vendor questionnaire is filled and vendor audit is done and complied.

In case of excipients and secondary packing material questionnaire is  completed.(if required, audit to   be carried out)

When manufacturing site audit is required, it shall be carried out by site QA/CQA to assess compliance with cGMP requirements.

The manufacturing site of the vendor shall be audited as per the checklist.

Based on the audit findings, a detailed report shall be classified as critical(C), Major (M) and minor (N) as described under definitions.

The purchase department shall send the site audit report prepared by site QA/CQA to the vendor. The vendor should respond in a period of 30 days after receipt of the audit report from purchase department.

The audit compliance report received from the new vendor shall be evaluated by the audit team members and recommendations shall be given to approve or reject the vendor by head QA.

Re-audit may be required for ensuring compliance in case of critical deficiencies observed during the audit.

QA shall update the vendor list once in 6 months to include or exclude approved vendor and to reflect the change in the status of vendors.

PERIODIC EVALUATION OF APPROVED VENDORS :

For approved vendor’s evaluation, following steps shall be followed:

Evaluation of the vendor’s quality performance shall be done once in a year. This annual evaluation

shall include review of rejection rate of the vendor’s lots and resolution of quality issues, if any

Yearly trending of all API from the Vendor shall be carried out of quality issues, if any.

Reassessment of quality systems shall be carried out if the rejection rate on quality grounds is higher than 20%.

All the vendor’s of API and primary packing materials shall be audited once in three years.

The vendor should respond with audit compliance report in a period of 30 days after receiving the audit report from purchase department.

If the compliance is not satisfactory, then the vendor rating will be downgraded or disapproved and deleted from the list. QA will update the vendor list accordingly and communication of the same shall  be sent to QC, warehouse and purchase department.

DISQUALIFICATION OF VENDORS :

Vendors failing to meet the GMP requirements and those consistently (up to three lots) failing to meet quality standards shall be disqualified and blocked for supply of material by QA. However vendor can immediately be disqualified, Incase of any critical failure e.g. failing in potency (Assay below 80 %), microbial test (failure in pathogens). If the satisfactory corrective actions are taken by the vendor to resolve the quality problems and non- compliances, the vendor shall be re-approved for the supply.

FLOW CHART OF VENDOR APPROVAL

What is Quality Management system :

A Quality management system (QMS) is the core of any quality and compliance process. It is a regulatory requirement that the Food and Drug Administration (FDA) and other global regulatory bodies consider critical. An automated QMS system reduces audit time and findings and lowers the risk of product recalls. It improves product quality and safety, increases customer satisfaction and ensures FDA and ISO compliance.

Pharmaceutical Quality professionals are facing more challenges, and have more opportunities to improve quality and compliance than ever before. Mergers and acquisitions, complex supply chains, data integrity issues, and tightening regulations are all forces that affect pharmaceutical quality strategies and processes on a day-to-day basis. Plus, the FDA and other regulatory bodies are increasingly focused not only on compliance, but on the importance of building a culture of Quality management in the pharmaceutical industry.

An effective pharmaceutical Quality management system (QMS) will help you develop a culture of quality, support data integrity, keep suppliers under control, and maintain overall compliance. QMS data must also be structured to drive consistent metrics, risk calculations, and other trend analysis.

What is the Purpose of Quality Management system :

AQ management system can be defined as a collection of business processes that are focused on meeting customer requirements on a consistent basis. This may seem simple enough, however, it is essential that certain obstacles are overcome for your QMS to be successful.

With this in mind, ask yourself the following questions:

• Do the same mistakes keep on being repeated?
• Is there lack of visibility between each of your departments?
• Do you have a high customer churn rate, negative customer reviews or perhaps a declining bottom line?

If you answered yes to any of the above, it may be that your QMS is not working as it should be.

The purpose of a quality management system is to ensure every time a process is performed, the same information, methods, skills and controls are used and applied in a consistent manner. If there are process issues or opportunities, this is then fed into the quality management system to ensure continuous improvement.

Importance of Quality Management System:

Here are reasons why quality management systems are so important for pharmaceutical companies:

Lessen the Risk of Errors :

The most obvious reason to invest in a QMS is to assist your company to reduce errors made when producing products. Without an advanced system where all employees involved understand their roles and responsibilities and communicate with each other, there will be more chance that errors will be made. Pharmaceutical companies of all sizes are at risk of doing mistakes without QMS in place. With an advanced QMS in place, everyone understands the tasks they need while completing a project. And, what steps ought to be taken each time to lessen the risk of errors from occurring.

Cut Costs with Quality Management System :

Errors can result in the wastage of products and money for your company. Not only are you wasting money on scraping products with errors that don’t meet the standards they require, but also you are wasting your employee’s time. Redo the work because of errors takes time far from other important tasks that still ought to be complete. As an advanced QMS, it streamlines production, makes it more efficient, and helps everyone involved become more productive. Also, companies may be able to see an increase in profits as well.

Encourage you to Constantly Upgrade :

Implementing an advanced QMS is a great place to begin, but the work doesn’t end there. The current system which you are using is unlikely to remain consistent, which is really a good thing. A quality management system encourages companies to keep them updated to improve their operations and makes it easier to identify areas where you ought to change. Technologies may also change, requiring you to adapt and upgrade your system to run more smoothly.

Customer Satisfaction :

Improving your company’s efficiency and production process are huge benefits to having an advanced QMS in place. However, the foremost important goal of all pharmaceutical companies is to make products that will help customers to live better. Ensuring that you’re producing high-quality products that are thoroughly checked over throughout the whole production process means you’re delivering better products to your customers. Customer satisfaction is more important for the companies, as they give your company positive reviews, which leads to increase sales.

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Below are the responsibilities of Engineering personnel in Pharmaceutical Industry (But not limited To)

1. To follow Good Engineering Practice.

2.Preparation and Review of departmental SOPs

3. Preparation and Review of PM schedule, checklist and attending breakdown.

4. Observation and Guideline in installation activities of new equipment’s or projects at site.

5. Implementation of SAP

6. To review and undertake audits of vendor quality management system.

7. Review and implementation of Technical Agreement.

8. New vendor developments for different engineering services and follow up.

9.To witness calibration and validation activities and review of calibration certificates.

10. Support in installation activities of equipment’s.

11. Validation and Review of Site master plan and Coordination with contract persons

12.Preparing all drawings and related system engineering documents, such as :

P & I drawings

Utility drawing such as HVAC, Water system

Building and Room Drawings

Maintenance Requirements

Operational Manuals

Equipment Component Identification

Identification of Calibration Requirements

Equipment Installation and System Construction Procedures.

13. Co-ordination of the calibration activities for all critical instruments as identified by the validation team.

14. Executing, Installation Qualification and Operational Qualification tasks and assisting in the execution of Performance Qualification.

15. Maintenance of process & utility equipment.

16. Responsible for handling of change control, deviation, and incidents within the department.

17. To ensure the ALCOA Data Integrity Checks.

Introduction :

Annex 11 requires that audit trails are regularly reviewed to ensure data integrity. There are a significant amount of inconsistent interpretations about the requirement to regularly review audit trails. Some of the interpretations are that a periodic review of audit trails should be performed to ensure data integrity. Under a periodic review approach some companies have implemented a monthly, quarterly, bi-annual and yearly review of audit trails. The challenge is how relevant it is to perform a periodic review after an extended period of time when the data was generated. What is the value? What are we supposed to be looking for? What constitutes a data integrity issue? Which data is critical? Should we take a risk based approach?

This article will provide answers to these challenging questions and solutions about how to perform regularly audit trail reviews.

The Challenges :

Aligning with the requirement to regularly perform audit trails reviews can be very challenging for some companies. This requirement is based on the assumption that all system provide audit trails that are “user friendly”, adequate and easy to review for data integrity. One of the biggest challenges is that some systems specifically in the Quality Control laboratories don’t generate audit trails that facilitate a review regularly. Another challenge is whether to perform periodic review or to assess the audit trails prior to signing or approving the data. Can we implement the same approach for all areas with GMP impact or can we take a risk based approach. Which approaches are more value added and not just a paper work exercise?  

Unfortunately Annex 11 and other data integrity philosophies fail to provide adequate guidance and direction about how to regularly review audit trails. There is always the challenge on how to deal with all the assumptions related to this requirement and this also includes resources to regularly review audit trails. In order to review audit trails regularly qualified resources are needed to perform this work. The resource impact needs to be clearly understood based on the population of impacted systems, the volume of the reviews and the defined frequency. All the potential challenges need to be well understood and addressed prior to committing to perform audit trails reviews, otherwise the effort will be meaningless and simply a paper exercise. 

Audit Trail Assessments :

In order to align with the requirement to regularly review audit trails an assessment needs to be performed for all impacted systems. The audit trail assessment is the first and the most critical steps to implement audit trail reviews. An inventory of all impacted systems need to be created. This inventory will identify all impacted systems that need to be included in the audit trail assessment. The intent of the assessment is to identify whether each individual system provide audit trails that are adequate and that can be used for performing these reviews. 

System level risk assessments need to be performed to identify whether the system is high, medium or low risk. The system risk needs to be used to prioritize the audit trail assessment and implementation of periodic reviews. For example a quality control system to measure critical quality attributes is probably high risk and should be a priority. A risk based approach will be discussed in more detail later in this article.

Each functional area that have GxP computer systems need to perform the audit trail assessment to determine the following:

• Who has access to view the audit trails?
• Can the audit trail be printed from the application?
• Can the reviewer select a data range?
• Can the reviewer select a specific activity of interest during the audit trail review?
• Will it feasible to include the audit trail with the data results?
• Will it be feasible for QC systems to include the audit trail with the assay results?
• Are user’s action time and date stamped?
• Does the audit trail records creation, modification and deletion of records?

The answer to each question will be potentially being different for each system assessed. Based on the results of this assessment remediation activities may be required to address any gaps or improvements need for audit trails.

To document the results of the audit trail assessment a summary report should be created to summarize the findings.

A remediation plan should be created to describe the corrective actions that will be taken for each system.

Once all remediation activities are closed procedures need to be created or revised to include the steps for performing audit trails periodic review. 

Risk based Approach :

A risk based approach to audit trail reviews is critical for an implementation that provide a meaningful process without having a negative impact on cost and resources. The fact is that without taking a risk based approach audit trail reviews can have a negative impact on cost and resources. Audit trail reviews for GxP systems are a time consuming activity that requires resources to execute and manage the information an actions related to the review.

In order to take a risk based approach to audit trail reviews the system risk level need to be identified. Prioritizing the audit trail assessment based on the level of risk is critical to prioritize the assessments and implementation. Systems involved in the testing of Critical Quality Attributes are high risk and should be the highest priority during the assessments and implementation.

The system risk level should be used to establish the frequency and scope of the audit trails periodic reviews. For high risk systems such as those used in Quality Control the audit trails should be reviewed with the test results to ensure the integrity of the test data. The scope of this review should include assessing the accuracy and integrity of the data using the audit trail. In this situation the audit trail will be reviewed for the following:

• Changes to test parameters
• Changes to data processing parameters
• Data deletion
• Data modifications
• Analyst actions
• Data manipulation
• Excessive integration of chromatography peaks
• Security breaches related to data 

QC procedures need to define the controls related to data integrity; this will ensure consistency during the audit trail review. 

For medium and low risk systems the approach will be less intensive that for high risk. For these systems it can be possible to review periodically the audit trails. The periodic review period should be established based on the level of system risk. Medium risk systems should be reviewed more frequently than low risk systems. For example a document management system is probably medium risk that should be on a periodic review schedule of every six months or a yearly schedule. Low risk system can be reviewed on a yearly or bi-annual basis. 

The scope of the audit trail reviews for medium and low risk systems should include the following: 

• Data changes
• Data deletions
• Unauthorized access or transactions

To implement audit trail reviews is critical to take a risk based approach. A one size fits all approach can have a significant impact on cost and resources. 

In summary a risk based approach is critical for the implementation of audit trail periodic reviews.

Implementation :

Once the audit trail assessment are performed, system risk identified and all corrective actions are closed the audit trail reviews can be implemented. Prior to implementation the impact to resource need to be well understood based on the expected volume of work. Once this impact is understood hiring and reassigning of resource need to be completed prior to formal implementation.

Procedure may need to be created or revised to include the approach of audit trails reviews for each system based on the results of the assessment and system risk.

The last step is training all impacted resources on the applicable procedures with an emphasis of data integrity. 

Summary :

Annex 11 requires that audit trails are reviewed regularly to ensure data integrity. The frequency and scope of the audit trail reviews is not defined in annex 11. Audit trails periodic reviews have impact on resources and cost. To minimize the cost and resource impact and risk based approach should be taken for the implementation of audit trails review. The approach should be based on the system risk level which will facilitate defining scope and frequency of the reviews.

An audit trail review when properly implemented can increase the integrity of data generated by GxP systems.

Reference : https://www.gmp-compliance.org/guidelines/gmp-guideline/eu-gmp-annex-11-computerised-systems

1.         OBJECTIVE             

1. To laydown a procedure for the cleaning, storage, usage and maintenance of packing machine change parts.

2.         RESPONSIBILITY   

• Technical Assistant – Cleaning/storage/Maintenance of packing machine change Parts.

• Executive  – Responsible for Cleaning/storage/Maintenance of packing  machine change parts.

3.         PROCEDURE                       

CLEANING

3.1.1    Dismantle the change parts from the machine.

3.1.2 Clean the change parts, using lint free dry cloth.

3.1.3    Check the change parts removed from the machine and keep the change  parts in the rack provided.

3.1.4    Affix a cleaned label to the change parts.

3.1.5    Clean and lubricate the change gears.

3.1.6    Clean other parts with lint free cloth.

3.1.7 Frequency of cleaning for all the change parts which comes into contact with the product – For every three batches (of similar products), or after  every batch (for different products), or weekly (if machine is in operation) or monthly (if machine is idle) which ever is the earlier and as and when required.

3.1.8 Frequency of cleaning the change parts, which do not come into contact with the product – after every product change over or every month if machine is idle.

 STORAGE

At all times when not in use the change parts shall be stored in racks duly identified.

 USAGE

 NOTE: Handle all the change parts carefully during assembling and dismantling.

Size changeover is always done after complete dismantling of the change parts previously used.

Assemble all the change parts after cleaning of the machine.

MAINTENANCE

Incoming inspection – Engineering department shall receive the change  parts from the supplier and subject them to the inspection. Any sets not  conforming to the specifications are returned to the supplier for the replacement.

On receipt of the change parts into the department the production personnel shall inspect the parts, identify them with the appropriate number.

If any damage occurs to the change parts it should be immediately intimated to the maintenance department for corrective action.

Record the details in change parts record

Precautions: Take care that critical parts like blow head, counter-sealing roller of  Blister packing machine, sealing rollers of strip packing machine, punching tool, embossing tools are kept in safe area.

 Collect properly the embossing rollers & keep them in safe area.

4.         ABBREVIATIONS   

            Nil

5.         REFERENCES          

            Nil

6.         ANNEXURES

            Change parts record

 

  1.0     OBJECTIVE             

1.1       To lay down a procedure for Preventive Maintenance of Auto Coater.

  2.0     RESPONSIBILITY                                                  

• All Tec. Assistants – To perform the preventive maintenance activities as per the respective SOP.

• All Executives (Eng.Dept.) – To prepare and comply the preventive maintenance SOP.

• All Department Heads – To implement and compliance of this SOP.

  3.0     PROCEDURE           

3.1 Weekly Maintenance

• Check all contactors and tighten the line connections.

• Check all solenoid valves and coils for proper working.

• Check the working of all PLC interlocks.

• Check the tightness of all fasteners, if required tighten all fasteners.

• Check for air leakages from PU tube and connectors, if found arrest the same.

• Check the working of steam trap, inlet air handling unit and dehumidifier.

• Check the working of steam control valve by changing the inlet set temperature values, if required repair / replace the control valve.

3.2 Monthly Maintenance

• Check the oil level in the gear box, if required refill with fresh oil up to the mark.

•   Check the pan supporting wheel bearings, if required lubricate the bearings.

•  Check the v-belt/chain tension, if required replace or adjust the v-belt/chain tension. (Wherever applicable)

• Clean the AHU pre filters and scrubber unit filters (wherever applicable) and scrubber unit chamber.

• Check the working of inlet and exhaust dampers and its solenoid valves, if required repair or replace it.

• Check the pneumatic actuators working condition and leakages, if required replace the gasket of the actuators.

• Check the gun bar pneumatic cylinder alignment, if required re-align the alignments and check the movement of the cylinder shaft.

• Check the working of steam control solenoid valves.

• Check the functioning of all inter locks.

• Check the working of compressor and its interlocks.(Wherever applicable)

• Clean the condenser coil, chilled water/evaporator coil and wet scrubber unit with water. (Wherever applicable)

• Check the working of condenser fan and its inter connections. (wherever applicable)

• Check the working of dehumidifier bed drive, if required clean the bed by passing the compressed air at 1kg/cm² from the reverse direction of air flow.

• Check the working of dehumidifier heaters, if required replace with new heater.

3.3 Yearly Maintenance

• Check the motor bearings condition, if required replace with new bearings.

• Drain the gear box oil and top up with fresh oil up to the mark.

• Check the condition of steam coil, if any leakages observed arrest them.

• Check the inlet and exhaust blowers working and clean, if required.

• Check the scrubber unit filters condition, if required replace with new filters.(Wherever applicable)

• Check the condition of HEPA filter for physical damage and integrity, if required replace the filter with new one.

• Check the steam control valves for proper functioning, if required replace the valves with new one.

• Check the condition of all gaskets and replace all gaskets once in year.

• Check the condition of dehumidifier bed, if required replace with new bed.

•  4. ABBREVIATIONS

• SOP  :-  Standard Operating Procedure

• AHU :- Air Handling Unit

• PU     :- Poly Urethane

• PLC   :- Programmable Logic Control

• HEPA:- High Efficiency Particulate Air

• 5. REFERENCES

5.1         SOP: Procedure for preventive maintenance

• 6. ANNEXURES

Annexure – 1    Weekly preventive maintenance checklist

Annexure – 2    Monthly preventive maintenance checklist

Annexure – 3   Yearly preventive maintenance checklist

Annexure  – 4    List of lubrication points and safety controls

 

1.         OBJECTIVE             

1.1       To lay down the procedure for Preventive Maintenance of Autoclave

2.         RESPONSIBILITY                                                  

• Assistant – Engineering &Production  – To follow the SOP

• Executive – Engineering & Production – To comply the SOP

3.         PROCEDURE

3.1       Monthly Maintenance

3.1.1     Check the Oil level in the FRL unit assembly and refill the oil with in the limits.

3.1.2     Check all electrical connections in the panel if required tight all screw fastenings

3.1.3 Check the steam traps for proper working, if not replace with new one.

3.1.4 Check the Air leakages from all PU connectors and PU tubes.

3.1.5 Check the functioning  of all solenoid valves, if it is not working properly clean the coil and plunger unit or replace the Coil.

3.1.6 Lubricate the synthetic grease to guide track of the door.

3.1.7 Check the leakages from the door gaskets, valves and from all joints.

3.2       Half Yearly Maintenance

3.2.1 Check the Solenoid valves and coils, clean the valves and if require replace the Coils

3.2.2 Check the Pneumatic cylinder seal kits if required replace the seals with new seals

3.2.3 Check the condition of Pneumatic actuators, if required replace with new one.

3.2.4 Check the actuator gaskets for leakages, if require replace with the new gaskets

3.2.5 Check the steam valves for leakages, if require replace the gaskets

3.2.6 Check the gland rope or mechanical seals of the WRVP for leakages if required replace the new gland ropes or Mechanical seals

3.2.7 Check the door Gaskets condition if require replace the with the new gaskets.

3.3 Yearly maintenance

3.3.1 Check the vacuum pump and motor bearings, if required replace the bearings.

3.3.2 Check the water leakage from the pump, if required replace the gland rope or mechanical seals

3.3.3 Check the safety valves working condition.

4. ABBREVIATIONS

• FRL     :     FILTER REGULATOR AND LUBRICATOR

• WRVP :     WATER RING VACUUM PUMP

• HPHV  :     HIGH PRESSURE HIGH VACUUM

5. REFERENCES

           NIL

6. ANNEXURES

• Annexure – 1    Monthly Preventive maintenance check lists

• Annexure – 2    Half yearly preventive maintenance check lists

• Annexure – 3    Yearly preventive maintenance check lists