What is change control ? Step by step handling of change control with examples ( Production department)

 In pharmaceutical production, change control is a crucial process that ensures any modifications to equipment, processes, or procedures are managed systematically and safely. Here are some examples of how change control is handled in the pharma industry:

Equipment Change: When a pharmaceutical company decides to replace or upgrade a critical manufacturing equipment, a formal change control process is initiated. It involves assessing the impact of the change, conducting risk assessments, and ensuring proper validation of the new equipment before implementation.

Process Change: If there is a need to modify a manufacturing process, change control is employed to evaluate the potential impact on product quality, safety, and efficacy. This process includes thorough documentation, testing, and validation to ensure the changes do not compromise product quality.

Raw Material Change: When there is a need to switch or modify a raw material used in drug manufacturing, change control is applied to evaluate the impact on the product's quality attributes and regulatory compliance. Any such change must be approved through a formal change control procedure.

Packaging Change: Pharmaceutical products are often subject to changes in packaging materials or design. Change control is employed to assess the impact on product stability, shelf life, and compatibility with the new packaging.

Change in Manufacturing Site: If a company decides to move production from one site to another, extensive change control measures are implemented to ensure the new facility meets regulatory requirements, maintains product quality, and prevents cross-contamination.

In all these examples, the change control process involves a thorough evaluation of potential risks, proper documentation, and adherence to regulatory guidelines to ensure patient safety and product quality are maintained throughout the changes.

The management of change control in pharmaceutical production involves a series of systematic steps to ensure that any modifications to equipment, processes, or procedures are evaluated, documented, and implemented in a controlled manner. Here are the typical steps in the change control process:

Initiation of Change Control Request: The process begins with the identification of a need for change, which could be due to various reasons such as process improvements, equipment upgrades, or regulatory requirements. The individual or department proposing the change initiates a change control request.

Change Proposal and Impact Assessment: A detailed change proposal is prepared, outlining the reasons for the change, its scope, and the intended benefits. An impact assessment is conducted to evaluate potential risks and impacts on product quality, safety, and regulatory compliance.

Change Control Review Board (CCRB): A Change Control Review Board or Committee, composed of cross-functional representatives, reviews the change proposal and impact assessment. The board ensures that all necessary aspects have been considered and evaluates the overall feasibility of the proposed change.

Approval and Authorization: If the Change Control Review Board approves the change, the proposal is formally authorized. The responsible personnel or department is assigned to implement and oversee the change.

Change Implementation Plan: A comprehensive implementation plan is developed, detailing the steps, resources, and timelines required to execute the change. This plan includes risk mitigation strategies and validation requirements.

Validation and Testing: Depending on the nature of the change, validation studies and testing may be conducted to ensure that the modified process or equipment functions as intended and meets the required quality standards.

Documentation and Records: Throughout the change control process, detailed documentation is maintained, including all change-related activities, decisions, and outcomes. This documentation is critical for regulatory compliance and audits.

Training and Communication: All relevant personnel are trained on the changes to ensure proper understanding and adherence to the new procedures. Effective communication is vital to keep all stakeholders informed during the implementation process.

Verification and Monitoring: After the change has been implemented, the process is monitored to ensure it performs as expected. This includes ongoing data collection and analysis to verify that the intended outcomes are achieved.

Closure and Review: Once the change is successfully implemented and verified, the change control process is formally closed. A post-implementation review is conducted to assess the effectiveness of the change and identify any lessons learned for future improvements.

By following these steps, pharmaceutical companies can effectively manage change control in production, ensuring product quality, safety, and compliance are maintained while facilitating continuous improvement in their operations.

What is Data integrity and ALCOA plus in pharmaceutical industry

 What is Data Integrity?

Data integrity is the maintenance of, and the assurance of, data accuracy and consistency over its entire life-cycle and is a critical aspect to the design, implementation, and usage of any system that stores, processes, or retrieves data.

Data integrity is a key approach in the pharmaceutical quality control system. ALCOA is (Attributable, Legible, Contemporaneous, Original, and Accurate) was introduced in the 1990s for ensuring the pharma industry as a framework for data integrity and Good documentation practice (GDP). Then further introduced ALCOA plus is (Complete, Consistent, Enduring and Available) Currently used by the FDA, WHO, PIC/S, and GAMP. So overtime periods, data integrity concepts expand from ALCOA to ALCOA plus for ensuring data security and integrity ( data protection) are observed and maintained.

ALCOA+

ALCOA has five basic principles (Attributable, Legible, Contemporaneous, Original, and Accurate) to stop data integrity issues.

Attributable:

The collected data must be attributed, who performs the action and when, if a record is changed, who did it and why? For example, when during conducting of validation, the test result must be dated, and the initial should be done by the person involved in conducting the test. If any change in the monitoring system, the change detail should be in the audit trail and any correction made by the person should be recorded and dated. A signature log must be for the identification of initials and the person who completed the paper record.

Legible:

Legible data means the data can be easily read. This attribute should be ensured both in the short and long term, therefore the materials used in recording and collecting the data should be durable.

Contemporaneous:

The data should be recorded at the time and date of work performed. The timestamp should we follow in order.

For example, when conducting validation protocol, the result of the test performed should be recorded in an online sequence. Recording the results should be dated with a timestamp then logged in the electronic system.

Original:

The information must be recorded as original or in a certified true or original copy; this may be an acceptable protocol or a database or a notebook.

For example validation test is being recorded on a given protocol because recording test results in a Notebook may be a chance of error. If the original data is handwritten, it must be stored in an electronic system.

Accurate

For data and records to be accurate, they should be free from errors, complete, truthful and reflective of the observation. Editing should not be performed without documenting and annotating the amendments.

For example:

• Use a witness check for critical record collection to confirm accuracy of data.
• Consider how to capture data electronically and verify its accuracy. Build accuracy checks into the design of the electronic system.
• Place controls/verification on manual data entry, for example, temperature results can only be entered within a predefined range of 0-100°C.

ALCOA PLUS (+)

Complete:- All data should be complete including, test repeat or re-analysis performed on the sample.

Consistent:-  Consistent in a generation of record and application of date and time stamps in the expected sequence.

Enduring:- Data should be recorded in a controlled worksheet in laboratory notebooks or invalidated Electronic systems.

Types of granulation in tablet formulation

TYPES OF GRANULATION
Granulation can be achieved by three method as follows :-
1. Direct compression   
      Crystalline substance like sodium chloride, sodium bromide may be compressed directly. The vast majority of medicinal agents are rarely so easy to tablet, direct compression material should posses good flow and compresibility and must be inert, tasteless, able to disintegrate and inexpensive.
Method
(Drug + filler + disintegrant + lubricant + glidant ) all are blend directly after sifting through Viber sifter and compressed


2. Dry Granulation
   It is used in situations where effective dose of a drug is too high for direct compaction and the drug is sensitive to heat, moisture, or both which preclude wet granulation. This is also called slugging method.
Method
A.      (Drug + filler + lubricant) All are.       blend then precompression done and     after that   comminution done
 
 B.  (glidant + lubricant + disintigrant)  sizing then blend with A

3. Wet Granulation
  Wet granulation forms the granules by binding the powders together with an adhesive, instead of by compaction. Liquid bridge are developed between particles, and the tensile strength of these bond increase as the amount of liquid binder added is increased. A drying process is required in all wet granulation to remove the solvent and to reduce the moisture content. After drying granulation is screened again, followed by compression.

Schematic drawing of All types granulation

GOOD DOCUMENTATION PRACTICES

Good documentation practice GDP is a systematic procedure of preparation, reviewing, approving, issuing, recording, storing and archival of any document.

THE IMPORTANCE OF DOCUMENTATION:

As per GMP "If it is not written down, then it did not happen". The document provides information on when, where, who, why and how to complete the task. The document provides evidence proving that the tasks have been completed as they should be.

BASIC REQUIREMENTS OF GDP:

1. Always record the entries at the time of activity simultaneously.

2. Always record date with signature in GMP records.

3. Always use an indelible ballpoint pen to record data in GMP records.

4. Always enter the data directly in the GMP records in the English language.

5. Never use a pencil or erasable or water-soluble ink pen to complete the GMP records.

6. Never use white ink or correction fluid to correct the entry in GMP records

7. Never sign for someone else on any document. Only sign for the work that you have performed yourself.

8. Never back date GMP records.

9. Never discard original raw data of any kind.

10. Never use scratch papers, loose papers or “post it” to record the data.

11. Never discard or destroy any GMP record unless retention period expiry is reached.

12. Documentation and records used throughout the manufacturing process, as well as supporting

processes, must meet the basic requirement of GDP.

List of such documents is provided below (List is not limited):

Batch records

Bill of Materials

Specifications

SOPs

Protocols

Test methods

Checklists

Forms / Log sheets

Training assessments

Certificate of Analysis

Technology transfer document

Validation documents

Maintenance records

Calibration records

GENERAL REQUIREMENTS

Below mentioned requirements should be applied to all the documentation within the GMP environment.

A. Clearly written documentation:

● All documents must be accurate and written in a manner that prevents errors and ensures consistency. 

● If documents are to be used together, e.g. a SOP and a form, then each should reference the other. 

● Ensure there is traceability between two or more documents/records using formal document numbers or record identification. 

B. Using indelible ink:

● All records must be filled out in indelible BLACK or BLUE ballpoint pen for long term legibility. 

● Do not use pencil or ink that can be erased.

C. Legible handwritten Entries:

● A document is unusable if it cannot be read, so care must be taken to ensure that handwriting is legible. All entries must be made at the time the tasks are performed and should be legibly signed and dated. 

● The same is true for electronic documents and records – language should be clear and unambiguous. 

D. Reviewing and approving:

● To ensure that the information is correct and accurate, documents and records should be reviewed by someone who has performed the task and has proper knowledge. A signature and date by the reviewer/approver confirm that a review has taken place. 

● Unsigned documents or records are incomplete and should not be used to perform any task or considered as evidence of a completed task

E. Employee signatures:

● Handwritten signatures must be unique to the individual and listed within the signature register to ensure that the signature is traceable to the concerned employee (or contractor).

● Any employee should not be permitted to sign for another member of staff unless delegated. Signatures must never be forged.

● The management of the signature record should be governed by a procedure and routinely reviewed so that it remains current – new employee should sign the signature register during induction, the signature register must indicate the date employee exit.

PREPARATION OF DOCUMENTS

1. Clear and concise titles should be used for headings, tables, graphs, etc.

2. Pages in the master document should be numbered as X of Y.

3. Full-text spelling with the abbreviation in brackets should be used for the first time. The abbreviation may be used in place of full-text spelling in the remainder of the document.

4. All documents should have the signature and date of the person who prepared the document, reviewed the document and approved the document.

5. All master documents should have an effective date, approval date, and current version number.

6. Respective SOPs should be followed while preparing the documents.

7. Words that everyone can understand should be used. Unfamiliar words reduce the reader’s understanding of what is written. Definitions of abbreviations should always be included in the document for reference. This is most effectively done by including the definitions in a table format, at the start or end of the document.

8. Ensure that the contents of the document are not squeezed into a smaller area just to limit page numbers. Documents with small margins and no spaces between paragraphs and headings can be difficult to look at, hard and slower to read. Space the contents out so that the type/font is easy to read for all users.

9. When creating a document, consider the context in which the document may be used in the future and whether the reader has enough background information.

10 People remember information best when there is a strong visual prompt, such as a diagram. When the document has to be lengthy, consider using tables to structure the information for the easy understanding of the reader.

11. Training of the document should be planned only after approval of document and shall be completed before the effective date.

ISSUANCE AND RETRIEVAL OF GMP RECORDS

1. All the forms associated with the activity should be part of respective SOPs.

2. QA maintains the list of GMP impacting forms and its associated SOP.

3. Records for issuance and retrieval of such forms should be maintained.

RECORDING THE TIME AND DATE IN GMP RECORDS

1. Time should be entered in 24:00-hour cycle. Record the time in HH: MM format. For Example 11:05 AM should be written as 11:05 and 11:05 PM should be written as 23:05.

2. The date should be entered in DD.MM.YY format. For example, 27th July 2013 should be written as 27.07.13.Place “0” before the digit if the digit is less than 10 for the recording of date.

DATA RECORDING IN THE GMP RECORDS

1. Date and time should be recorded in GMP records as mentioned above.

2. Data should be recorded only in the format duly issued and approved by Quality Assurance.

3. Entries in the logbooks should be made in chronological order. Entries should never be pre-completed.

4. Data recording should be done by trained and authorized person.

5. Data should be recorded as it is displayed on the respective equipment panel.

6. Unusual observation during the activity should be recorded, signed and dated. Same should be reported to area person in-charge and QA.

7. If any observation/signature/date are to be repeated, the same should be rewritten. Ditto (----“---) marking or “as above” or “do” should not be used.

8. Manual entries should be reviewed and signed by the second person for accuracy and completeness.

9. Raw data/print outs generated during the activity should be signed at the left bottom with date and should be attached to relevant records. Printouts made on the thermal paper should be photocopied. Thermal paper copy along with photocopy should be attached to the concerned record.

CORRECTION OF ENTRY IN GMP RECORDS

1. Incorrect entries in GMP records should not be overwritten or blocked to make it unreadable.

Always use a single strike out line (For example: Incorrect Entry) to mark the incorrect entry in such a manner that entry remains readable.

2. Correct entry should be written near to the strikeout entry. Person correcting the entry should put the initial signature and date along with corrected entry. Only the person who made the original entry and strikethrough should make the correction. If this is not possible, notify to QA.

3. The reason for correcting the entry should also be documented on the record. In the case of space constraint in the document, the reason for correction should be mentioned on the footer of the record with (*) sign.

HANDLING OF MISSING ENTRY IN GMP RECORDS

1. Entries in the GMP records should be done contemporaneously with the activity. However, the procedure mentioned below should be followed in the exceptional case of missing entry in GMP records.

2. Missing entry in the GMP records can be re-entered later if the data are retrievable. (For example: start time of blender is missed by the operator, however, the entry for the same is mentioned in the equipment usage log)

3. In such case, an entry should be made with a clear indication of the date when the activity was performed and the date the activity is recorded on the document.

4. Document the explanation to substantiate the entry and the reason for the delay in recording.

5. Missing entry in the GMP records for non-retrieval data should be handled through event investigation procedure (For example, operator missed the reading of drying temperature during the operation, where there is no automatic data recording mechanism in place).

WORKING WITH BLANK OR UNUSED SPACE

Blank/Unused space in the GMP records should be strikeout as below with single line with sign and date to ensure that record cannot be added to a later date.

CANCELLATION OF GMP RECORDS

Cancellation of GMP records should only be allowed in the rare case with the approval of QA and in exceptional cases such as spillage of chemical on the record. Event investigation procedure should be followed to determine further course of action. The reason for cancellation should be documented for cancellation of the document and signed by area person in-charge and QA.