PERSONNEL - Personnel Qualifications

There should be an adequate number of personnel qualified by appropriate education, training, and/or experience to perform and supervise the manufacture of intermediates and APIs.

The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing.

Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular operations that the employee performs and GMP as it relates to the employee's functions.

Records of training should be maintained. Training should be periodically assessed.

Personnel Hygiene 

Personnel should practice good sanitation and health habits.

Personnel should wear clean clothing suitable for the manufacturing activity with which they are involved and this clothing should be changed, when appropriate. Additional protective apparel, such as head,

face, hand, and arm coverings, should be worn, when necessary, to protect intermediates and APIs from contamination.

Personnel should avoid direct contact with intermediates or APIs.

Smoking, eating, drinking, chewing and the storage of food should be restricted to certain designated areas separate from the manufacturing areas.

Personnel suffering from an infectious disease or having open lesions on the exposed surface of the body should not engage in activities that could result in compromising the quality of APIs. Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions should be excluded from activities where the health condition could adversely affect the quality of the APIs until the condition is corrected or qualified medical personnel determine that the person's inclusion would not jeopardize the safety or quality of the APIs.

Consultants 

Consultants advising on the manufacture and control of intermediates or APIs should have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained.

Records should be maintained stating the name, address, qualifications, and type of service provided by these consultants.

Internal Audits (Self Inspection) & Product Quality Review

To verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule.

Audit findings and corrective actions should be documented and brought to the attention of responsible management of the firm. Agreed corrective actions should be completed in a timely and effective manner.

Product Quality Review (2.5)

Regular quality-reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually and should include at least:

· A review of critical in-process control and critical API test results

· A review of all batches that failed to meet established specification(s)

· A review of all critical deviations or nonconformances and related investigations

· A review of any changes carried out to the processes or analytical methods;

· A review of results of the stability monitoring program

· A review of all quality-related returns, complaints and recalls

· A review of adequacy of corrective actions

The results of this review should be evaluated and an assessment made of whether corrective action or

any revalidation should be undertaken. Reasons for such corrective action should be documented.

Agreed corrective actions should be completed in a timely and effective manner.

Responsibility for Production Activities

The responsibility for production activities should be described in writing and should include, but not necessarily be limited to:

1. Preparing, reviewing, approving, and distributing the instructions for the production of

intermediates or APIs according to written procedures 

2. Producing APIs and, when appropriate, intermediates according to pre-approved

instructions

3. Reviewing all production batch records and ensuring that these are completed and signed

4. Making sure that all production deviations are reported and evaluated and that critical

deviations are investigated and the conclusions are recorded

5. Making sure that production facilities are clean and, when appropriate, disinfected

6. Making sure that the necessary calibrations are performed and records kept

7. Making sure that the premises and equipment are maintained and records kept

8. Making sure that validation protocols and reports are reviewed and approved

9. Evaluating proposed changes in product, process or equipment

10. Making sure that new and, when appropriate, modified facilities and equipment are

qualified

Responsibilities of the Quality Unit

The quality unit(s) should be involved in all quality-related matters.

The quality unit(s) should review and approve all appropriate quality-related documents.

The main responsibilities of the independent quality unit(s) should not be delegated. These

responsibilities should be described in writing and should include, but not necessarily be limited to:

1. Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the

control of the manufacturing company

2. Establishing a system to release or reject raw materials, intermediates, packaging, and

labeling materials

3. Reviewing completed batch production and laboratory control records of critical

process steps before release of the API for distribution

4. Making sure that critical deviations are investigated and resolved

5. Approving all specifications and master production instructions

6. Approving all procedures affecting the quality of intermediates or APIs

7. Making sure that internal audits (self-inspections) are performed

8. Approving intermediate and API contract manufacturers

9. Approving changes that potentially affect intermediate or API quality

10. Reviewing and approving validation protocols and reports

11. Making sure that quality-related complaints are investigated and resolved

12. Making sure that effective systems are used for maintaining and calibrating critical

equipment

13. Making sure that materials are appropriately tested and the results are reported

14. Making sure that there is stability data to support retest or expiry dates and storage

conditions on APIs and/or intermediates, where appropriate

15. Performing product quality reviews 

Principles for Quality Management

Quality should be the responsibility of all persons involved in manufacturing.

Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of anagement and appropriate manufacturing personnel.

The system for managing quality should encompass the organizational structure, procedures, processes and resources, as well as activities to ensure confidence that the API will meet its intended specifications for quality and purity. All quality-related activities should be defined and documented.

There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. The quality unit can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.

The persons authorized to release intermediates and APIs should be specified.

•All quality-related activities should be recorded at the time they are performed.

•Any deviation from established procedures should be documented and explained. Critical deviations

•should be investigated, and the investigation and its conclusions should be documented.

•No materials should be released or used before the satisfactory completion of evaluation by the quality

•unit(s) unless there are appropriate systems in place to allow for such use (e.g., release under quarantine

•as described in Section X (10) or the use of raw materials or intermediates pending completion of

•evaluation).

•Procedures should exist for notifying responsible management in a timely manner of regulatory

•inspections, serious GMP deficiencies, product defects and related actions (e.g., quality-related

complaints, recalls, and regulatory actions).

Format for standard operating procedures (SOPs)

This section of the guide presents a basic format for an SOP with instructions on what information should be provided. It also gives information for the design of data record forms. Several specific SOPs have been presented in this format, and instructions and examples have been presented indicating the type of information which should be included for other types of SOPs.

The formats and sample SOPs can be used, modified, or redesigned by each manufacturer according to their organizational structure, and by the complexity of their manufacturing operations.

The information in the format is essentially an SOP describing "How to Write an SOP".

Format for a standard operating procedure (SOP)

Standard operating procedures (SOPs)

Standard operating procedures (SOPs) are the detailed written instructions that specify how a test or administrative procedure is to be performed, or how a piece of equipment is operated, maintained and calibrated. SOPs describe the "standard" approved procedures that are routinely carried out in a GMP facility. They indicate exactly how things are done, and are kept current by review and approved revision on a predetermined schedule (usually annual), or when planned changes are made to the procedure or equipment and reagents used in the procedure. 

The original of a current version of an SOPs is maintained in a central file, and copies are distributed to the locations where the procedure is performed. The procedure for describing the writing, revising and approving of SOPs and the control of distribution of SOPs is one of the important quality assurance procedures. The term “change control” has recently been introduced to the vocabulary of pharmaceutical manufacturing and control.

Although this is primarily a term for validation procedures, it may also apply to the control of the review and revision of SOPs for routine procedures. Any SOP describing the distribution and control of documents must clearly indicate the mechanisms by which SOPs can be modified or changed: from assessment and rationale for the need for a change, to the evaluation of other SOPs that might be changed as a result, to the final approval of changes and the implementation of the changed procedure. SOPs are used as a reference by the persons responsible for the performance, and are also used for training new operators in the performance of the procedure. Quality assurance procedures

should be in place to ensure that SOPs are enforced and properly used.

SOPs follow a scientific format, and are written with the view that they will be used by persons trained in the procedure. They should be specific instructions for each step in sequential order including the preparatory work which must be done before starting the main procedure, as well as instructions for recording and reporting the results. There is little need for excess text on theory and background - what is required is clear concise instructions for carrying out a procedure which has been approved.

Usually the initial draft of an SOP is written by the person performing the procedure or by someone who knows the procedure well and must be written including the details and the time course of the tasks. Supervisors review the SOPs for completeness and content and QC or QA staff approve for regulatory compliance. When appropriate, a formal data sheet or data record form is prepared for an SOP.

This form is a parallel summary document with checklists, checkboxes, and blanks for all data to be recorded during the performance of the procedure. It also has spaces for signatures of the operator and other technicians who verify and countersign certain critical operations during the procedure. Finally, there is the space for the signature of the department supervisor who reviewed the completed data record form. Such blanks WHO/VSQ/97.01 13 and checklists ensure that the required data are collected, that nothing is overlooked and also provide the evidence that the procedure was performed according to the SOP.

The datasheets also provide instructions for recording deviations to the procedure, for calculations or reporting requirements, for comparison of results with predetermined specifications, and the criteria for repeating procedures in cases where unacceptable results were obtained.

Range of requirements for written procedures

Throughout the WHO GMP Guidelines, in addition to sections on document requirements, many references are made to the need for written procedures for specific aspects of the manufacturing process. There is a broad range of SOPs needed for a pharmaceutical manufacturing establishment. GMP Guidelines and Regulations for pharmaceuticals, sterile products, and biologicals from WHO, the EU and several other countries make reference to ‘written procedures” throughout the documents.

In Appendix 2 of this Guide, a list of the titles of the SOPs from three vaccine manufacturers is presented to give an idea of the SOPs needed by a manufacturer.A review of WHO’s GMP Requirements for reference to "written procedures" resulted in a long list of operations and activities which must follow written approved procedures. The list covered the requirements for all aspects of the control of quality raw materials and packaging materials, the premises, the equipment, the test procedures, the production, personnel performance, and quality assurance. Appendix 1 of this Guide lists a range of the types of procedures which should be prepared in written format. Others may be required depending on the products manufactured, on the size of operations, and on the management structure of the company.

DOCUMENTATION TYPES & GUIDELINES

ü  Standard operating procedures, specifications and master formulae

Descriptive documents give instructions on how to perform a procedure or a study, or

give a description of specifications. The instruction type documents are: standard

operating procedures (SOP); protocols (for validation studies, stability studies, safety

studies); and master formulae (manufacturing instructions). Each of these gives instruction

on how to perform specific procedures. Specifications describe the required

characteristics or composition of a product or material or test. These kinds of documents

provide the specific details defining the quality of incoming materials, the quality

of the production environment, the quality of the production and control process,

and the quality of the final product.

ü  Forms for recording data

Another type of documentation is the form used for recording data as it is taken during

the performance of tasks, tests, or events. These are forms (datasheets, or data

record forms), reports, batch processing records, and equipment log books. These

documents provide the evidence that the raw materials, facility environment, the production

process, and the final product consistently meet the established quality requirements.

ü  Identification numbers

There are also the identification systems or codes devised to number and track both

information and documents. These are SOP numbers, equipment numbers, form numbers,

receiving codes, and batch/lot numbers. These numbering systems should be

designed so that procedures, processes and materials can be traced throughout the data

records.

ü  Labels

Labelling systems are used to identify the status of the equipment or facility, restricted

areas, and warning labels. These include raw material tags, quarantine labels, release

labels, reject labels, labels to identify specific storage areas, biohazard or radioactive

labels, restricted access labels, equipment "cleaned" or "waiting for cleaning" labels,

process intermediate labels, and the final product labels. These permit the identification

and tracking of materials, of the progress of a production process, and assurance

of the proper functioning of equipment.

The WHO guidelines for Good Manufacturing Practices (ref. 21, 27) and all other

national and international GMP Guidelines and Regulations (ref. 3, 5, 7, 11, 18, 19)

emphasize the requirement for complete documentation. A well-structured documentation

system, including SOPs for the regular document review and revision, provides

the structure for recording the evidence for the quality of the product.

All documentation must be organized into files which must be maintained for specified

periods of time after the expiry date of the product.

A well-designed documentation system is useful only if it is well used. The system

must include quality assurance procedures to ensure that instructions are followed,

that labels and numbering systems are properly used and recorded, and that data record

forms and batch processing records are assembled and reviewed. Control and assessment

of the documentation system itself is a significant management tool that permits

an ongoing assessment of the changes and revisions necessary to remain in compliance,

to delete what is unnecessary or redundant and to improve procedures or processes.

Ref: WHO/VSQ/97.01 11

Reasons for Documentation

1. Consistent Control over the Operation

Documentation communicativeness information concerning a wide range of activities carried out during pharmaceutical manufacture and control operations, providing detailed and  clear instructions. Written statements, whether on hard copy or generated electronically and viewed on a screen, avoid the risk of misinterpretation inherent in oral communication.

2. Consistent Training


3. Regulatory Requirement


4. Permanent Traceable Record


5. Control of Deviation and Change

Types of Pharmaceutical Documentation

Five Basic types of documents will be described in the monograph, and key requirements for each will be outlined.


1. Policy Documents


Policy Documents give the company overview of what will be done, who is accountable for ensuring it is done, and company organisation to aid continuing with policy.


2. Specifications


Specifications are documents which describe starting materials, packaging materials, intermediate, bulk or finished product in terms of their chemical, physical and when appropriate biological characteristics. A specification normally includes descriptive clauses and numerical clauses and numerical clauses, which define standards and permitted tolerances.


3. Procedures


Procedures are formal written instructions which detail how an operation is to be performed. They are requires for all operation which can effect the safety, identity, quality and purity standards of medicinal products. Such documents are often termed 'SOPs' or Standard Operating Procedures.


4. Work Instructions


Work Instructions are batch- related documents which list all the starting materials to be used and the production operation.


5. Records


Records are completed documents, reports, instructions, protocols, logbooks etc., which are used to record information. They provide a history of each batch of product together with data pertinent to the quality of the final product.

About Documentation

Documentation is the key to operating a pharmaceutical company in compliance with

GMP requirements. The system of documentation devised or adopted should
 have as its main objective to establish, monitor, and record "quality" for all aspects 
of the production and quality control. Several types of documents are needed to 
accomplish this. ( As per WHO)